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Understanding the Role of Systemic Inflammation in Alzheimer’s Disease

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Abstract

Human and animal studies suggest that inflammation occurring outside the central nervous system (systemic inflammation) may play a key role in promoting neurodegeneration, Alzheimer’s disease pathology, and cognitive decline in older adults. Systemic inflammation, which is marked by increased blood levels of circulating proinflammatory cytokines and chemokines, may occur as a result of events such as infection, chronic disease, and physical and psychological stress, but may also occur outside the context of these conditions as a result of subclinical processes such as cellular senescence. Proinflammatory cytokines within the body can promote a proinflammatory environment in the central nervous system by crossing the blood-brain barrier, signaling through endothelial cells or circumventricular organs, and by stimulating the vagus nerve, which signals the detection of inflammatory proteins via direct afferent connections to the brain stem. Through each of these routes, systemic inflammation is believed to induce reactive, proinflammatory microglia and astrocytic phenotypes which can promote tau hyperphosphorylation, β-amyloid oligomerization, complement activation, and the breakdown of neurotransmitters into potentially harmful bioactive metabolites. Together, these molecular changes are believed initiate or exacerbate neurodegenerative processes that can eventually lead to cognitive decline and dementia in vulnerable older adults.

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... It can be defined as the presence of systemic inflammatory cell stress products including cytokines and other inflammatory mediators, and also by the complexity of various mediators in the plasma (Zotova, Chereshnev et al. 2016). Systemic inflammation is marked by increased circulating pro-inflammatory cytokines, including interferons (IFNs), IL-1β, IL-6, TNF-α, IL-8, IL-18, and chemokines such as MCP-1 (Walker et al. 2019;Lin et al. 2020). The Gram-negative bacterial product LPS is widely used to develop animal models of both local and systemic inflammation (Seemann et al. 2017), and can induce cytokine storm (excessive production of pro-inflammatory cytokines) (Ramos-Benitez, Ruiz-Jimenez et al. 2018;Zhao et al. 2019). ...
... Circulating cytokines are considered important mediators of the gut-brain communication, as they can reach the CNS through multiple neural and humoral pathways, including via vagal afferent signaling, transcytosis of cytokines through blood-vessel walls into circumventricular organs, and receptor-mediated transcytosis of cytokines across the blood-brain barrier Leclercq et al. 2017;Hillemacher et al. 2018;Walker et al. 2019) and stimulate microglia, the resident macrophage-like innate immune cells of the CNS which are distinct from the peripheral macrophages that infiltrate the brain (Jurga et al. 2020). During development, microglia play a critical role in non-immune tasks that are essential for brain development and function (synaptic remodeling, pruning, angiogenesis promotion) and in the adult brain the microglia surveil the microenvironment in an inactive state until activated into a functional phenotype among a broad spectrum of possible phenotypes (Lenz and Nelson 2018). ...
... As a result, microglia and supportive astrocytes are activated by pro-inflammatory cytokines circulating in the blood, and turn into a reactive pro-inflammatory phenotype to produce pro-inflammatory cytokines, proteases and chemokines and cause neuroinflammation. Although microglia also differentiate into an antiinflammatory phenotype to stop inflammation and restore homeostasis of the microenvironment, persistent activation of pro-inflammatory microglia has been implicated in many neurodegenerative diseases (Walker et al. 2019). ...
Article
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The human digestive tract contains a diverse and abundant microbiota that is important for health. Excessive alcohol use can disrupt the balance of these microbes (known as dysbiosis), leading to elevated blood endotoxin levels and systemic inflammation. Using QIAGEN Ingenuity Pathway Analysis (IPA) bioinformatics tool, we have confirmed that peripheral endotoxin (lipopolysaccharide) mediates various cytokines to enhance the neuroinflammation signaling pathway. The literature has identified alcohol-mediated neuroinflammation as a possible risk factor for the onset and progression of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), and psychiatric disorders such as addiction to alcohol and other drugs. In this review, we discuss alcohol-use-induced dysbiosis in the gut and other body parts as a causal factor in the progression of Central Nervous System (CNS) diseases including neurodegenerative disease and possibly alcohol use disorder. Graphical Abstract
... Of note, it became increasingly clear that inflammation, peripheral and central, are important (and often early) events in AD progression. 34,35 In agreement with this, our recent publication entangles different mechanisms behind the interplay between peripheral inflammation and AD brain pathology. 36 Recently, we also reviewed the current understanding of how systemic inflammatory processes can affect brain pathology. ...
... Kitazawa et al. and Quintanilla et al. reported that proinflammatory cytokines led to Tau phosphorylation by increasing the activity of Tau kinases. 69,70 Besides, phosphorylation of Tau is enhanced by quinolinic acid (QA) 35 a downstream metabolite of tryptophan that is formed by the kynurenine pathway involving the enzyme indoleamine-2,3oxygenase (IDO). The activity of IDO and the level of QA appear to be elevated in AD patients. ...
... 71 This could be owing to viral infection, because IDO activity in immune cells is increased upon inflammation. 35 . ...
Article
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder for which only symptomatic medication is available, except for the recently FDA-approved aducanumab. This lack of effective treatment urges us to investigate alternative paths that might contribute to disease development. In light of the recent SARS-CoV-2 pandemic and the disturbing neurological complications seen in some patients, it is desirable to (re)investigate the viability of the viral infection theory claiming that a microbe could affect AD initiation and/or progression. Here, we review the most important evidence for this theory with a special focus on two viruses, namely HSV-1 and SARS-CoV-2. Moreover, we discuss the possible involvement of extracellular vesicles (EVs). This overview will contribute to a more rational approach of potential treatment strategies for AD patients. Teaser: The recent SARS-CoV-2 pandemic and the disturbing neurological complications in a significant number of COVID-19 patients brought the viral infection theory as a possible cause for AD back into the spotlight. Here, we give a vision on the latest evidence for this theory.
... Additionally, studies have demonstrated chronic and systemic immune activation in offspring following prenatal exposure to MIA (Hsiao et al., 2012;Rose et al., 2017). Human and animal studies suggest that systemic inflammation reflected by peripheral inflammatory cytokines may be linked to the exacerbation of neurodegenerative diseases such as AD and cognitive decline in older adults (Walker et al., 2019;Ashraf-Ganjouei et al., 2020). However, it is unknown whether MIA exposure in utero increases systemic inflammation in aged offspring. ...
... Alterations in inflammatory cytokine, NGPF2, and PSD-95 are associated with cognitive dysfunction in aged mice with accelerated aging Chronic systemic inflammation increases the risk of cognitive impairment (Ashraf-Ganjouei et al., 2020). Specifically, systemic inflammation ultimately activates microglia and astrocytes via different pathways, contributing to AD pathology and age-related cognitive decline (Walker et al., 2019). In current study, elevated levels of IL-6, IL-1β, and TNF-α were positively associated with poorer cognition, especially in aged LPS and LPS-EE mice, demonstrating that increased systemic inflammation is closely related to cognitive decline during the accelerated aging. ...
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Introduction Research suggests that prenatal inflammatory exposure could accelerate age-related cognitive decline that may be resulted from neuroinflammation and synaptic dysfunction during aging. Environmental enrichment (EE) may mitigate the cognitive and synaptic deficits. Neurite growth-promoting factor 2 (NGPF2) and postsynaptic density protein 95 (PSD-95) play critical roles in neuroinflammation and synaptic function, respectively. Methods We examined whether this adversity and EE exposure can cause alterations in Ngpf2 and Psd-95 expression. In this study, CD-1 mice received intraperitoneal injection of lipopolysaccharide (50 μg/kg) or normal saline from gestational days 15–17. After weaning, half of the male offspring under each treatment were exposed to EE. The Morris water maze was used to assess spatial learning and memory at 3 and 15 months of age, whereas quantitative real-time polymerase chain reaction and Western blotting were used to measure hippocampal mRNA and protein levels of NGPF2 and PSD-95, respectively. Meanwhile, serum levels of IL-6, IL-1β, and TNF-α were determined by enzyme-linked immunosorbent assay. Results The results showed that aged mice exhibited poor spatial learning and memory ability, elevated NGPF2 mRNA and protein levels, and decreased PSD-95 mRNA and protein levels relative to their young counterparts during natural aging. Embryonic inflammatory exposure accelerated age-related changes in spatial cognition, and in Ngpf2 and Psd-95 expression. Additionally, the levels of Ngpf2 and Psd-95 products were significantly positively and negatively correlated with cognitive dysfunction, respectively, particularly in prenatal inflammation-exposed aged mice. Changes in serum levels of IL-6, IL-1β, and TNF-α reflective of systemic inflammation and their correlation with cognitive decline during accelerated aging were similar to those of hippocampal NGPF2. EE exposure could partially restore the accelerated decline in age-related cognitive function and in Psd-95 expression, especially in aged mice. Discussion Overall, the aggravated cognitive disabilities in aged mice may be related to the alterations in Ngpf2 and Psd-95 expression and in systemic state of inflammation due to prenatal inflammatory exposure, and long-term EE exposure may ameliorate this cognitive impairment by upregulating Psd - 95 expression.
... In the past two decades, mounting evidence implicates neuroinflammation as an important contributor to AD pathogenesis [45]. In addition, non-steroidal anti-inflammatory drugs have been reported to reduce the risk of developing AD, even though their preventive effects remain still to be fully demonstrated [46]. ...
... Particularly, we sought to link the cardanol skeleton, which might interact with the PAS through its aromatic end, with a fragment able to fish the CAS, to obtain dual binding AChE inhibitors (Figure 7) [81]. As a CAS key molecular feature, we selected fragments bearing a cationic head, which included a protonatable amino moiety belonging to different systems: heterocyclic amines such as pyrrolidine (25), piperidine (26), morpholine (27), thiomorpholine (28), N-substituted piperazines (29)(30)(31)(32)(33), hydroxylated pyrrolidine (34) and piperidines (35)(36)(37) and their corresponding O-acetyl (38)(39)(40)(41) and O-dimethylcarbamates (42)(43)(44)(45). Since the N-ethyl-N-(2-methoxybenzyl)amino moiety has been successfully exploited by us and others to obtain powerful dual binding AChEIs [82][83][84][85][86][87], we also synthesized hybrids 46-48 (Figure 7). ...
Article
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Alzheimer’s disease (AD) is a complex neurodegenerative disorder with a multifaceted pathogenesis. This fact has long halted the development of effective anti-AD drugs. Recently, a therapeutic strategy based on the exploitation of Brazilian biodiversity was set with the aim of discovering new disease-modifying and safe drugs for AD. In this review, we will illustrate our efforts in developing new molecules derived from Brazilian cashew nut shell liquid (CNSL), a natural oil and a byproduct of cashew nut food processing, with a high content of phenolic lipids. The rational modification of their structures has emerged as a successful medicinal chemistry approach to the development of novel anti-AD lead candidates. The biological profile of the newly developed CNSL derivatives towards validated AD targets will be discussed together with the role of these molecular targets in the context of AD pathogenesis.
... In a study conducted by Suridjan I. et al., and including patients with Alzheimer's disease, the presence of neuroinflammation detected by [18F]-FEPPA was positively correlated with the level of cognitive decline [72]. There is growing evidence that the presence of inflammation outside the central nervous system (systemic inflammation) can also contribute to a decline in cognitive functions [73]. According to Walker K. et al., elevated inflammatory markers in middle adulthood resulted in significant cognitive decline after 20 years [74]. ...
... SGLT2 inhibitors have been proven to strongly promote macrophage polarization towards M2 and thus alleviate inflammation and atherosclerosis (Table 1) [42]. In the central nervous system, M1 polarization of glial cells was associated with neurodegeneration [73]. M1 polarized macrophages activate STAT-1, which is a proinflammatory transcription factor [87]. ...
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Patients with diabetes are at higher risk of cardiovascular diseases and cognitive impairment. SGLT2 inhibitors (Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin, Sotagliflozin) are newer hypoglycemic agents with many pleiotropic effects. In this review, we discuss their neuroprotective potential. SGLT2 inhibitors (SGLT2i) are lipid-soluble and reach the brain/serum ratio from 0.3 to 0.5. SGLT receptors are present in the central nervous system (CNS). Flozins are not fully SGLT2-selective and have an affinity for the SGLT1 receptor, which is associated with protection against ischemia/reperfusion brain damage. SGLT2i show an anti-inflammatory and anti-atherosclerotic effect, including reduction of proinflammatory cytokines, M2 macrophage polarization, JAK2/STAT1 and NLRP3 inflammasome inhibition, as well as cIMT regression. They also mitigate oxidative stress. SGLT2i improve endothelial function, prevent remodeling and exert a protective effect on the neurovascular unit, blood-brain barrier, pericytes, astrocytes, microglia, and oligodendrocytes. Flozins are also able to inhibit AChE, which contributes to cognitive improvement. Empagliflozin significantly increases the level of cerebral BDNF, which modulates neurotransmission and ensures growth, survival, and plasticity of neurons. Moreover, they may be able to restore the circadian rhythm of mTOR activation, which is quite a novel finding in the field of research on metabolic diseases and cognitive impairment. SGLT2i have a great potential to protect against atherosclerosis and cognitive impairment in patients with type 2 diabetes mellitus.
... It has been proposed that neuroinflammation is a possible cause or driving force of AD by contributing to neurodegeneration and pathogenesis across all stages of the disease [3]. AD is a systemic disease that involves a dynamic peripheral and central immune responses [4], and growing studies have shown a pivotal contribution of the peripheral immune system. Previous studies have reported changes in the peripheral immune systems of AD patients, especially in aspects of the cell count of neutrophils (NEU) and lymphocytes (LYM) as well as neutrophil-lymphocyte ratio (NLR). ...
... Although the detailed roles the immune system plays in AD are not fully understood and controversial, existing studies have shown a direct communication between the peripheral and central immune system [4,14], and the changes observed in the peripheral blood are a reflection of the immune response in the brain mediated by proinflammatory cytokines that are released to the periphery. A recent study showed that a history of infections requiring hospitalization was associated with future development of AD [15], and existing meta-analysis found that non-steroidal anti-inflammatory drug users had a lower risk of developing AD compared with nonusers [16]. ...
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Background Neuroinflammation has been considered to be a driving force of Alzheimer’s disease. However, the association between peripheral immunity and AD has been rarely investigated. Methods Separate regression analyses were conducted to explore the associations among peripheral immune markers and cognition, neuroimaging, and AD pathology. Causal mediation analyses were used to investigate whether the associations with cognition were mediated by AD pathology. Results A total of 1107 participants (43.9% female, mean age of 73.2 years) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included. Regression analyses indicated that elevated neutrophils (NEU) count and neutrophil-lymphocyte ratio (NLR) were associated with lower levels of global cognition, memory function (MEM), and executive function (EF), and reduced brain metabolism by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) as well as greater ventricular volume. An elevated NLR was associated with a lower level of β-amyloid (Aβ) and a higher level of total tau (T-tau) in cerebrospinal fluid (CSF), smaller hippocampal volume (HV), and lesser entorhinal cortex (EC) thickness. On the contrary, an elevated level of lymphocytes (LYM) was associated with a higher level of Aβ and a lower level of T-tau in CSF, better cognition, and less atrophy of brain regions (ventricular volume, HV, and EC thickness). The associations of LYM and NLR with cognition were mediated by Aβ and T-tau pathology (proportion: 18%~64%; p < 0.05). Conclusions We revealed that two types of peripheral immune cells (NEU and LYM) and the ratio of these two cell types (NLR) had associations with cognition, neuroimaging, and AD pathology. The associations might be mediated by Aβ and tau pathology.
... Interestingly, there is a convergence of the effects of small endogenous peptides such as VIP, substance P, and other cationic peptide drugs on mast cell activation via the Mas-related gene X2 receptor (MrgprX2) pathway [149], suggesting the presence of common pro-inflammatory pathways evoked by neuropeptides. Inflammatory processes have been reported to enhance tissue damage and accelerate the pathology of numerous neurological disorders including AD [150][151][152][153], stroke [154,155], Parkinson's disease (PD) [156,157], amyotrophic lateral sclerosis (ALS) [158], Huntington's disease (HD) [159], and neuropathic pain [160], as well as metabolic disorders such as obesity [161,162] and normal aging [163], all of which have been reported to display altered levels or function of neuropeptides. VIP has been heavily implicated in the regulation of the inflammatory response in the periphery (a comprehensive review can be found by Hooper and Kong (2015) [164]). ...
... These disrupt the BBB by inducing tight junction modifications, endothelial damage, astrocyte changes, and degradation of the glycocalyx and glia limitans, as reviewed by Varatharaj and Galea [174], and hence promoting proinflammatory processes in the brain [151]. Another way in which these inflammatory mediators cause neuronal damage is via the degradation of tryptophan into harmful intermediate metabolites, which can directly cause dysfunction of neurotransmitter receptors and modulate redox processes and the activity of immune cells [152]. Interestingly, the upregulation of neuropeptides β-endorphin, orexin, and oxytocin has been shown in rats during the systemic inflammatory response to acute pancreatitis [177], and this process appears independent of and earlier than the release of cytokines from microglia, indicative of a role of neuropeptides in the earliest stages of inflammation. ...
Article
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Despite recent leaps in modern medicine, progress in the treatment of neurological diseases remains slow. The near impermeable blood-brain barrier (BBB) that prevents the entry of therapeutics into the brain, and the complexity of neurological processes, limits the specificity of potential therapeutics. Moreover, a lack of etiological understanding and the irreversible nature of neurological conditions have resulted in low tolerability and high failure rates towards existing small molecule-based treatments. Neuropeptides, which are small proteinaceous molecules produced by the body, either in the nervous system or the peripheral organs, modulate neurological function. Although peptide-based therapeutics originated from the treatment of metabolic diseases in the 1920s, the adoption and development of peptide drugs for neurological conditions are relatively recent. In this review, we examine the natural roles of neuropeptides in the modulation of neurological function and the development of neurological disorders. Furthermore, we highlight the potential of these proteinaceous molecules in filling gaps in current therapeutics.
... [37][38][39] It is known that the progression of AD is related to a decline in the microglia's phagocytic activity and in an increase in the levels of proinflammatory cytokines and neurotoxic molecules. Although Aβ deposition may give rise to an inflammatory process by itself, traumatic brain injury, obesity, and systemic inflammation may provide a sustained neuroinflammatory stimulus that promotes the development of AD. 5,40 Systemic Inflammation AD may be considered a systemic disease since it comprises inflammation in the brain and inflammatory reactions in the periphery. 41 Cytokines are produced during systemic inflammation that can cross the BBB and signal to the CNS through the glial barrier by stimulating the vagus nerve. ...
... The overloading of kinases that induce tau hyperphosphorylation, complement-mediated synapse phagocytosis, β-amyloid oligomerization, as well as stimulation of the NLRP3 inflammasome, are activated by the continuous inflammatory process of microglia and astrocytes, causing neurodegeneration. 3, 6,40,42 junctions; (ii) the blood-leptomeningeal barrier (BLMB) that contacts with the cerebrospinal fluid (CSF) and has an unfenestrated endothelium connected by tight junctions; (iii) the blood-cerebrospinal fluid (blood-CSF) barrier that is composed by endothelial cells of the plexuses choroidal blood vessels that are connected by tight junctions. 46 The BBB has low permeability, and the passage of molecules depends on their physicochemical characteristics and interaction with endogenous efflux transporters, ie, ATP binding cassette transporters. ...
Article
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Current treatments for Alzheimer's disease (AD) attenuate the progression of symptoms and aim to improve the patient's quality of life. Licensed medicines are mostly for oral administration and are limited by the difficulty in crossing the blood-brain barrier (BBB). Here in, the nasal route has been explored as an alternative pathway that allows drugs to be directly delivered to the brain via the nasal cavity. However, clearance mechanisms in the nasal cavity impair the delivery of drugs to the brain and limit their bioavailability. To optimize nose-to-brain delivery, formulations of lipid-based nanosystems, namely nanoemulsions and nanostructured lipid carriers (NLC), formulated in situ gelling hydrogels have been proposed as approaches for nose-to-brain delivery. These formulations possess characteristics that facilitate drug transport directly to the brain, minimizing side effects and maximizing therapeutic benefits. It has been recommended that the manufacture of these drug delivery systems follows the quality by design (QbD) approach based on nasal administration requirements. This review provides an insight into the current knowledge of the AD, highlighting the need for an effective drug delivery to the brain. Considering the mounting interest in the use of nanoemulsions and NLC for nose-to-brain delivery, a description of drug transport pathways in the nasal cavity and the application of these nanosystems and their in situ hydrogels through the intranasal route are presented. Relevant preclinical studies are summarised, and the future prospects for the use of lipid-based nanosystems in the treatment of AD are emphasized.
... 3 Neuroinflammation can result from systemic inflammation triggered by peripheral infections or chronic conditions; thereby, systemic inflammation is thought to contribute to the onset of sAD. 4,5 The majority of the AD drug candidates have failed at the early phase of clinical trials, which raised questions about the use of therapeutic strategies and the relevance of animal models to reproduce cellular and molecular mechanisms underlying AD. 6 The preclinical models mimicking the disease can facilitate drug development by improving the predictability of drug candidate pharmacodynamics and pharmacokinetics in AD patients from preclinical data. One of the commonly used models for AD drug candidate testing is a transgenic APP swe /PS1dE9 (APdE9) mouse overexpressing the Swedish mutation of b-amyloid precursor protein (APP) and presenilin 1 (PSEN1) deleted in exon 9. 7 The APdE9 mouse reproduces several AD-related features, i.e., formation of Ab plaques, deficits in neuronal activity, mild neuritic abnormalities, impairment of preand postsynaptic cholinergic transmission, and elevated mortality, and therefore can be useful in the development of drug candidates targeting Ab plagues. ...
Article
Alzheimer's disease (AD) is an incurable disease, with complex pathophysiology and a myriad of proteins involved in its development. In this study, we applied quantitative targeted absolute proteomic analysis for investigation of changes in potential AD drug targets, biomarkers, and transporters in cerebral cortices of lipopolysaccharide (LPS)-induced neuroinflammation mouse model, familial AD mice (APdE9) with and without LPS treatment as compared to age-matched wild type (WT) mice. The ABCB1, ABCG2 and GluN1 protein expression ratios between LPS treated APdE9 and WT control mice were 0.58 (95% CI 0.44 – 0.72), 0.65 (95% CI 0.53 – 0.77) and 0.61 (95% CI 0.52 – 0.69), respectively. The protein expression levels of other proteins such as MGLL, COX-2, CytC, ABCC1, ABCC4, SLC2A1 and SLC7A5 did not differ between the study groups. Overall, the study revealed that systemic inflammation can alter ABCB1 and ABCG2 protein expression in brain in AD, which can affect intra-brain drug distribution and play a role in AD development. Moreover, the inflammatory insult caused by peripheral infection in AD may be important factor triggering changes in GluN1 protein expression. However, more studies need to be performed in order to confirm these findings. The quantitative information about the expression of selected proteins provides important knowledge, which may help in the optimal use of the mouse models in AD drug development and better translation of preclinical data to humans.
... However, how this communication occurs and at what stages it is beneficial or deleterious are unclear. Possible routes of communication between the peripheral and central compartments include circumventricular organs, direct transport across the blood-brain barrier (BBB) and stimulation of vagal afferents (reviewed in detail elsewhere [85][86][87] ). Current technology limits in vivo study of the mechanisms behind the clinical findings in humans, but animal studies of immune dysregulation provide critical insight into possible mechanisms of central-peripheral immune crosstalk and its temporal dynamics in AD. ...
Article
Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates that pathological alterations in central and peripheral immune responses that change over time. Considering AD as a systemic immune process raises important questions about how communication between the peripheral and central compartments occurs and whether this crosstalk represents a therapeutic target. We established a whitepaper workgroup to delineate the current status of the field and to outline a research prospectus for advancing our understanding of peripheral–central immune crosstalk in AD. To guide the prospectus, we begin with an overview of seminal clinical observations that suggest a role for peripheral immune dysregulation and peripheral–central immune communication in AD, followed by formative animal data that provide insights into possible mechanisms for these clinical findings. We then present a roadmap that defines important next steps needed to overcome conceptual and methodological challenges, opportunities for future interdisciplinary research, and suggestions for translating promising mechanistic studies into therapeutic interventions.
... The pathogenesis of AD is still enigmatic and complicated. Many factors, such as loss of acetylcholine (ACh) 3,4 , aggregation of Ab 5 , hyperphosphorylation of tau protein 6 , disturbance of biometallic homeostasis 7 , oxidative stress 8 , neuroinflammation, and activation of microglia cells 9 , are all considered to play a pivotal role in the pathogenesis of AD and possess complicated interconnections. The recognised multifactorial nature of AD and its consequent complexity is thought to account for the absence of effective drugs based on a single target. ...
Article
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A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d, benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe³⁺ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC50 = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d. In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment.
... This leads to comprehensive disease models and novel treatment approaches. Keenan and his colleagues suggested that systemic inflammation triggered the neurological disorders within the brain by opening the BBB permeability (Walker et al., 2019). If we can make systemic delivery of rAAV vectors to trace pathological changes of other tissues in neurodegenerative disease models, this may improve our understanding of neurodegenerative pathways, and even discover the linkage between systemic inflammation and neurological disorders. ...
Article
Neurodegeneration is the most common disease in the elderly population due to its slowly progressive nature of neuronal deterioration, eventually leading to executive dysfunction. The pathological markers of neurological disorders are relatively well-established, however, detailed molecular mechanisms of progression and therapeutic targets are needed to develop novel treatments in human patients. Treating known therapeutic targets of neurological diseases has been aided by recent advancements in adeno-associated virus (AAV) technology. AAVs are known for their low-immunogenicity, blood-brain barrier (BBB) penetrating ability, selective neuronal tropism, stable transgene expression, and pleiotropy. In addition, the usage of AAVs has enormous potential to be optimized. Therefore, AAV can be a powerful tool used to uncover the underlying pathophysiology of neurological disorders and to increase the success in human gene therapy. This review summarizes different optimization approaches of AAV vectors with their current applications in disease modeling, neural tracing and gene therapy, hence exploring progressive mechanisms of neurodegenerative diseases as well as effective therapy. Lastly, this review discusses the limitations and future perspectives of the AAV-mediated transgene delivery system.
... Increased production of inflammatory cytokines and chemokines, including IL-1β, promote breakdown of the blood brain barrier (BBB), which typically protects the CNS resident cells from harmful agents and inflammatory mediators (Cunningham, 2013;Bendorius et al., 2018;Yong et al., 2019). However, if there is a BBB breach, these soluble mediators can stimulate CNS resident astrocytes and microglia which, upon activation, amplify inflammatory conditions in the CNS that can cause significant damage to both infected and uninfected neurons as well as resident glial cells (Holmes, 2013;Paouri and Georgopoulos, 2019;Walker et al., 2019). Importantly, neurotropic infections can lead to harmful neuroinflammation that has been identified as a potential risk factor for neurodegenerative diseases (Monastero et al., 2014;Itzhaki, 2017;Sochocka et al., 2017;Fulop et al., 2018). ...
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Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, comprise a family of disorders characterized by progressive loss of nervous system function. Neuroinflammation is increasingly recognized to be associated with many neurodegenerative diseases but whether it is a cause or consequence of the disease process is unclear. Of growing interest is the role of microbial infections in inciting degenerative neuroinflammatory responses and genetic factors that may regulate those responses. Microbial infections cause inflammation within the central nervous system through activation of brain-resident immune cells and infiltration of peripheral immune cells. These responses are necessary to protect the brain from lethal infections but may also induce neuropathological changes that lead to neurodegeneration. This review discusses the molecular and cellular mechanisms through which microbial infections may increase susceptibility to neurodegenerative diseases. Elucidating these mechanisms is critical for developing targeted therapeutic approaches that prevent the onset and slow the progression of neurodegenerative diseases.
... neurodegenerative disorders have been closely associated with SCI (Libby, 2006;Kressel et al., 2009;Grivennikov et al., 2010;Ferrucci and Fabbri, 2018;Walker et al., 2019). While acute inflammation is a protective mechanism, SCI appears to be health damaging, having significant impact on the rise of many non-communicable physical and mental problems that dominate global rates of morbidity and mortality in the modern society (Bennett et al., 2018). ...
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One of the major clinical manifestations of peripheral neuropathy, either resulting from trauma or diseases, is chronic pain. While it significantly impacts patients’ quality of life, the underlying mechanisms remain elusive, and treatment is not satisfactory. Systemic chronic inflammation (SCI) that we are referring to in this perspective is a state of low-grade, persistent, non-infective inflammation, being found in many physiological and pathological conditions. Distinct from acute inflammation, which is a protective process fighting against intruders, SCI might have harmful effects. It has been associated with many chronic non-communicable diseases. We hypothesize that SCI could be a predisposing and/or precipitating factor in the development of chronic pain, as well as associated comorbidities. We reviewed evidence from human clinical studies indicating the coexistence of SCI with various types of chronic pain. We also collated existing data about the sources of SCI and who could have it, showing that those individuals or patients having SCI usually have higher prevalence of chronic pain and psychological comorbidities. We thus elaborate on the need for further research in the connection between SCI and chronic pain. Several hypotheses have been proposed to explain these complex interactions.
... These cytokines can lead to a pro-inflammatory environment in the central nervous system by entering the brain through the blood-brain barrier. Systemic inflammation can give rise to reactive, proinflammatory microglia and astrocytic phenotypes, that can also bring about tau hyperphosphorylation and Aβ amyloid oligomerization (55). A pro-inflammatory state has also been shown to directly contribute to the risk of coagulation and may additionally contribute to the risk for cerebrovascular events observed in T2DM (56). ...
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the most common cause of dementia. Over a third of dementia cases are estimated to be due to potentially modifiable risk factors, thus offering opportunities for both identification of those most likely to be in early disease as well as secondary prevention. Diabetes, hypertension and chronic kidney failure have all been linked to increased risk for AD and dementia and through their high prevalence are particularly apt targets for initiatives to reduce burden of AD. This can take place through targeted interventions of cardiovascular risk factors (shown to improve cognitive outcomes) or novel disease modifying treatments in people with confirmed AD pathology. The success of this approach to secondary prevention depends on the availability of inexpensive and scalable methods for detecting preclinical and prodromal dementia states. Developments in blood-based biomarkers for Alzheimer's disease are rapidly becoming a viable such method for monitoring large at-risk groups. In addition, digital technologies for remote monitoring of cognitive and behavioral changes can add clinically relevant data to further improve personalisation of prevention strategies. This review sets the scene for this approach to secondary care of dementia through a review of the evidence for cardiovascular risk factors (diabetes, hypertension and chronic kidney disease) as major risk factors for AD. We then summarize the developments in blood-based and cognitive biomarkers that allow the detection of pathological states at the earliest possible stage. We propose that at-risk cohorts should be created based on the interaction between cardiovascular and constitutional risk factors. These cohorts can then be monitored effectively using a combination of blood-based biomarkers and digital technologies. We argue that this strategy allows for both risk factor reduction-based prevention programmes as well as for optimisation of any benefits offered by current and future disease modifying treatment through rapid identification of individuals most likely to benefit from them.
... Accumulating evidence has linked systemic inflammation, as indicated by increased blood levels of circulating proinflammatory cytokines, to decreasing cognitive health and risk of dementia, especially in the later part of life [1]. Systemic inflammation can lead to cognitive decline and dementia by leading the proinflammatory environment in the central nervous system to induce reactive, proinflammatory microglia and astrocytic phenotypes, leading to tau hyperphosphorylation, β-amyloid oligomerization, complement activation, and the breakdown of neurotransmitters into potentially harmful bioactive metabolites [3]. Depletion of estrogen due to menopausal transition is also associated with a decline in cognitive health in women [4,5]. ...
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In postmenopausal women (PW), estrogen depletion may predispose to cognitive decline through an increased risk of chronic inflammation. Unhealthy diets also appear to have an impact on the cognitive health of these women. The aim of this study was to investigate the association between inflammatory potential of the diet, levels of inflammatory biomarkers, and cognitive function in PW. In a population of 222 PW, energy intake-adjusted Dietary Inflammatory Index (E-DII) was used to assess the dietary inflammatory potential. Cognitive function was estimated using the Polish version of Mini-Mental State Examination (MMSE), corrected by age and educational level. Selected biochemical inflammatory markers (C-reactive protein, CRP; interleukin-6, IL-6; and tumor necrosis factor alpha, TNF-α) were measured by ELISA tests. PW with an anti-inflammatory diet (first tercile) had significantly higher MMSE, while BMI, percentage fat mass and TNFα concentration were significantly lower compared to those with the most proinflammatory diets (third tercile). Women with cognitive impairment had significantly higher IL-6 concentrations (4.1 (0.8) pg/mL vs. 2.5 (0.2) pg/mL, p = 0.004), and were less educated (12.7 (0.7) years vs. 14.1 (0.2) years, p = 0.03) and less physically active compared to cognitively normal women. PW with the most proinflammatory diets had increased odds of cognitive impairment compared to those with the most anti-inflammatory diets, even after adjustment (OR = 11.10, 95% confidence level; 95%CI: 2.22; 55.56; p = 0.002). Each one-point increase in E-DII (as a continuous value) was also associated with 1.55-times greater odds of cognitive impairment (95%Cl: 1.19; 2.02 p = 0.003) in this population. Dietary inflammation may increase the risk of cognitive impairment in PW, but future studies should include a more sensitive battery of tests to assess cognitive function in this population. Implementation of an anti-inflammatory dietary pattern in PW may help prevent cognitive decline.
... It is noteworthy that the presence of mediators such as IL-1β, IL-6, IL-17, and TNF-α is important to determine in patients with AD as they represent a risk for their further progress (16,55). In this sense, low-grade inflammatory diseases are considered risk factors for the onset of AD (56)(57)(58)(59)(60). In fact, these mediators participate in the breakdown of the blood-brain barrier (BBB), which is compromised in patients with AD (56,59,61,62). ...
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Periodontitis is a low-grade inflammatory disease caused by a subgingival dysbiotic microbiota. Multiple studies have determined the higher prevalence of tooth loss and poor oral hygiene in patients with Alzheimer’s disease (AD). However, the periodontal diagnosis, periodontal bacteria or mediators has not been measured to date. Aim: To determine the periodontal status, the pro-inflammatory mediators, Porphyromonas gingivalis load, and Apoliporpotein E (ApoE) in patients with AD. A complete dental examination was performed on 30 patients, and cognitive status was determined by the Montreal Cognitive Assessment (MoCA). Subgingival microbiota and GCF samples were then taken from all patients from the deepest sites. Total DNA was isolated from the microbiota samples for the quantification of the 16S ribosomal subunit. Pro-inflammatory mediators and ApoE were quantified from the gingival crevicular fluid (GCF). Patients with AD had periodontitis stage III-IV in 80%, a higher concentration of pro-inflammatory and ApoE mediators, and a higher P. gingivalis load compared to healthy subjects. The pro-inflammatory mediators, P. gingivalis load had a negative correlation with the MoCA test scores. Finally, a ROC curve was performed to assess the specificity and sensitivity of ApoE levels, detecting an area of 84.9%. In AD patients, we found a more severe periodontitis, a higher levels of pro-inflammatory mediators, and higher bacterial load. In addition, there is an increase in ApoE that allows to clearly determine patients with health, periodontitis and periodontitis and AD.
... AD is a continuing and irreversible neurodegenerative disorder that gradually reduces memory and thinking skills, leading to the inability to perform simple daily tasks [23]. Inflammation in AD has been associated with circulating pro-inflammatory cytokines by stress and cellular senescence [58] and risk genes [59], mainly those expressed in microglia [60]. Microglial-derived cytokines are described to be neurotoxic, to support a chronic inflammatory milieu and to contribute to disease progression [26]. ...
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The prevalence of Alzheimer’s disease (AD), the most common cause of age-associated dementia, is estimated to increase over the next decades. Evidence suggests neuro-immune signaling deregulation and risk genes beyond the amyloid-β (Aβ) deposition in AD pathology. We examined the temporal profile of inflammatory mediators and microglia deactivation/activation in the brain cortex and hippocampus of 3xTg-AD mice at 3- and 9-month-old. We found upregulated APP processing, decreased expression of CD11b, CX3CR1, MFG-E8, TNF-α, IL-1β, MHC-II and C/EBP-α and increased miR-146a in both brain regions in 3-month-old 3xTG-AD mice, suggestive of a restrictive regulation. Enhanced TNF-α, IL-1β, IL-6, iNOS, SOCS1 and Arginase 1 were only present in the hippocampus of 9-month-old animals, though elevation of HMGB1 and reduction of miR-146a and miR-124 were common features in the hippocampus and cortex regions. miR-155 increased early in the cortex and later in both regions, supporting its potential as a biomarker. Candidate downregulated target genes by cortical miR-155 included Foxo3, Runx2 and CEBPβ at 3 months and Foxo3, Runx2 and Socs1 at 9 months, which are implicated in cell survival, but also in Aβ pathology and microglia/astrocyte dysfunction. Data provide new insights across AD state trajectory, with divergent microglia phenotypes and inflammatory-associated features, and identify critical targets for drug discovery and combinatorial therapies.
... In the United States, deaths due to Alzheimer's alone have increased by 33% in people aging 65 to 74 years, by 55% in people 75 to 84 years, and 78% in people 85 years and older (2020 Alzheimer's disease facts andfigures, 2020). It is seen that diseases that involve systemic inflammation, like infections, sepsis, and trauma, pose a risk to the deterioration of neurodegenerative disorders (Giridharan et al., 2019;Walker et al., 2019). The cytokine storm, along with the systemic inflammation caused by SARS-CoV-2, put these individuals in a similar boat. ...
Article
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Neurodegenerative disorders (NDD) are chronic neurological diseases characterized by loss and/or damage to neurons along with the myelin sheath, and patients are at higher risk of severe infection with the SARS-CoV-2. A comprehensive literature search was performed using relevant terms and inclusion-exclusion criteria. Recent articles, subjects older than 50 years, and articles written in the English language were included, whereas letters to the editor and articles related to pregnant women were excluded from the review study. COVID-19 appears to damage angiotensin-II receptors which cause natural killer cells to lose the ability to clear virus-infected cells, owing to worse outcomes in patients with NDD. COVID-19 can worsen the symptoms of Alzheimer's disease. In addition, COVID-19 worsens drug-responsive motor symptoms in Parkinson's disease (PD) and other symptoms like fatigue and urinary complaints. Vitamin D is essential in decreasing pro-inflammatory and increasing anti-inflammatory cytokines in ongoing COVID-19 infections and reducing angiotensin receptors and, hence, decreasing COVID-19 infection severity. Telemedicine shows promise for patients with NDD but is yet to overcome legal issues and personal barriers. COVID-19 has a significant effect on neurodegenerative conditions, which appears partly to the nature of the NDD and the neuro-invasive capabilities of the SARS-CoV-2. The protective role of vitamin D in patients with NDD further supports this hypothesis. Modifications in current health care, like the telemedicine platform, are required to address the increased risk of serious infection in this population. Further studies will be required to clarify conflicting reports in many fields.
... All these identified risk genes are involved in the regulation of the immune response within the central nervous system (CNS) but remarkably also outside the CNS. Moreover, epidemiological and translational research suggests that peripheral inflammation may promote AD pathology [67]. All these findings support a substantial involvement of both peripheral and central immune function in AD pathogenesis. ...
Article
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Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the accumulation of amyloid β (Aβ) and neurofibrillary tangles. The last decade, it became increasingly clear that neuroinflammation plays a key role in both the initiation and progression of AD. Moreover, also the presence of peripheral inflammation has been extensively documented. However, it is still ambiguous whether this observed inflammation is cause or consequence of AD pathogenesis. Recently, this has been studied using amyloid precursor protein (APP) overexpression mouse models of AD. However, the findings might be confounded by APP-overexpression artifacts. Here, we investigated the effect of low-grade peripheral inflammation in the APP knock-in ( App NL-G-F ) mouse model. This revealed that low-grade peripheral inflammation affects (1) microglia characteristics, (2) blood-cerebrospinal fluid barrier integrity, (3) peripheral immune cell infiltration and (4) Aβ deposition in the brain. Next, we identified mechanisms that might cause this effect on AD pathology, more precisely Aβ efflux, persistent microglial activation and insufficient Aβ clearance, neuronal dysfunction and promotion of Aβ aggregation. Our results further strengthen the believe that even low-grade peripheral inflammation has detrimental effects on AD progression and may further reinforce the idea to modulate peripheral inflammation as a therapeutic strategy for AD.
... Inflammation is a complicated protective response which encompasses changes in the host cellular and molecular components in order to eliminate the cause of cell injury [24] . Chronic inflammation is notoriously associated with a wide variety of diseases such as cancer [25] , arthritis [26] , diabetes [27] , Alzheimer's [28] and Parkinson [29] diseases. Several in-vitro and in-vivo research studies have indicated that classical NSAIDs have a proven ability to inhibit the proliferation of tumor through inducing apoptosis and affecting the microenvironment of the tumor [30] . ...
Article
A novel series of 19 quinoline/1,2,4-triazole hybrid 6a-i and 7a-j was synthesized and evaluated in vitro as dual COX-2/5-LOX inhibitors. Compounds 6e, 6i, and 7e displayed the highest potency and selectivity for inhibiting COX-2 activity (IC50 = 7.25, 8.13, and 8.48 nM, respectively; selectivity index (COX-1/COX-2) = 44.89, 30.30, and 33.47, respectively) in comparison to celecoxib (COX-2 IC50 = 42.60 nM; selectivity index (SI) = 8.05). The anti-inflammatory activity of the newly synthesized compounds was further examined in vivo using a carrageenan induced paw edema assay. Interestingly, the in vitro findings of the COX inhibitory assay were consistent with the in vivo assay. Moreover, 6e, 6i, and 7e showed a substantial reduction in serum concentrations of PGE2, TNF-α, IL-6. Molecular docking analysis of compounds 6e, 6f, 6i, 7e, and 7f revealed high binding affinities toward COX-2 compared to COX-1, which was matched with the experimental results. In addition, these compounds exhibited different binding orientations into the active site of COX-2, which were dependent on the type of substitutions on N4 of the triazole ring. Among the tested derivatives, compounds 6e, 6i and 7e which showed high selectivity to COX-2, exhibited hydrogen bonding interactions with key amino acids in COX-2 such as Arg120, Arg513, and/or Glu524. In addition, the tested compounds also showed multiple hydrogen bonds with the Arg101, Val110, Arg138 or His130 in 5-LOX. These findings show, taken together, that those derivatives are good leads to potential anti-inflammatory agents with lowest gastric damage.
... with all cause dementia. T2D and all cause dementia patients demonstrate systemic hyperglycemia, hyperlipidemia and hyperinsulinemia (may progress to hypoinsulinemia in insulin dependent diabetics) [28,92,105,[201][202][203][204][205][206][207][208][209][210][211][212][213][214][215][216][217][218][219][220]. T2D is characterized by the development of insulin resistance, a reduction in the sensitivity to insulin, promoted by overactivation of the insulin signaling cascade by chronically elevated insulin. ...
Article
Many people living with dementia and cognitive impairment has dysfunctional mitochondrial and insulin-glucose metabolism resembling type 2 diabetes mellitus and old age. Evidence from human trials shows that nutritional interventions and anti-diabetic medicines that target nutrient-sensing pathways overcome these deficits in glucose and energy metabolism and can improve cognition and/or reduce symptoms of dementia. The liver is the main organ that mediates the systemic effects of diets and many diabetic medicines; therefore, it is an intermediate target for such dementia interventions. A challenge is the efficacy of these treatments in older age. Solutions include the targeted hepatic delivery of diabetic medicines using nanotechnologies and titration of macronutrients to optimize hepatic energy metabolism.
... Multiple linear regression considering disease duration, age, sex, treatments, and comorbid conditions showed no significant interaction (Supplementary Table 3). To determine whether the neuroinflammation which occurs in both AD [129][130][131][132][133] and PD 77,134-137 could produce a similarly increased percentage of DAT + /TH + PBMCs that could be generalized to neurodegeneration, we repeated these experiments in a cohort of Alzheimer's diseases (AD) patients with no movement disorder, psychoses, and no use of dopaminergic drugs (i.e. neuroleptics, antidepressants). ...
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Parkinson’s disease (PD) is marked by a loss of dopamine neurons, decreased dopamine transporter (DAT) and tyrosine hydroxylase (TH) expression. However, this validation approach cannot be used for diagnostic, drug effectiveness or investigational purposes in human patients because midbrain tissue is accessible postmortem. PD pathology affects both the central nervous and peripheral immune systems. Therefore, we immunophenotyped blood samples of PD patients for the presence of myeloid derived suppressor cells (MDSCs) and discovered that DAT+/TH+ monocytic MDSCs, but not granulocytic MDSCs are increased, suggesting a targeted immune response to PD. Because in peripheral immune cells DAT activity underlies an immune suppressive mechanism, we investigated whether expression levels of DAT and TH in the peripheral immune cells marks PD. We found drug naïve PD patients exhibit differential DAT+/TH+ expression in peripheral blood mononuclear cells (PBMCs) compared to aged/sex matched healthy subjects. While total PBMCs are not different between the groups, the percentage of DAT+/TH+ PBMCs was significantly higher in drug naïve PD patients compared to healthy controls irrespective of age, gender, disease duration, disease severity or treatment type. Importantly, treatment for PD negatively modulates DAT+/TH+ expressing PBMCs. Neither total nor the percentage of DAT+/TH+ PBMCs were altered in the Alzheimer’s disease cohort. The mechanistic underpinning of this discovery in human PD was revealed when these findings were recapitulated in animal models of PD. The reverse translational experimental strategy revealed that alterations in dopaminergic markers in peripheral immune cells are due to the disease associated changes in the CNS. Our study demonstrates that the dopaminergic machinery on peripheral immune cells displays an association with human PD, with exciting implications in facilitating diagnosis and investigation of human PD pathophysiology.
... Epidemiological and translational studies have indicated that the peripheral systemic immune or inflammatory responses may promote neurodegenerative and AD-specific pathology [19]. For instance, systemic immune challenge by the lipopolysaccharide and chronic inflammatory disorders could result in the development of AD-like neuropathology and an increase in the risk of AD [20][21][22][23], respectively. ...
Article
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Background Alzheimer’s disease (AD), a progressive neurodegenerative disease, is the most common cause of dementia worldwide. Accumulating data support the contributions of the peripheral immune system in AD pathogenesis. However, there is a lack of comprehensive understanding about the molecular characteristics of peripheral immune cells in AD. Methods To explore the alterations of cellular composition and the alterations of intrinsic expression of individual cell types in peripheral blood, we performed cellular deconvolution in a large-scale bulk blood expression cohort and identified cell-intrinsic differentially expressed genes in individual cell types with adjusting for cellular proportion. Results We detected a significant increase and decrease in the proportion of neutrophils and B lymphocytes in AD blood, respectively, which had a robust replicability across other three AD cohorts, as well as using alternative algorithms. The differentially expressed genes in AD neutrophils were enriched for some AD-associated pathways, such as ATP metabolic process and mitochondrion organization. We also found a significant enrichment of protein-protein interaction network modules of leukocyte cell-cell activation, mitochondrion organization, and cytokine-mediated signaling pathway in neutrophils for AD risk genes including CD33 and IL1B . Both changes in cellular composition and expression levels of specific genes were significantly associated with the clinical and pathological alterations. A similar pattern of perturbations on the cellular proportion and gene expression levels of neutrophils could be also observed in mild cognitive impairment (MCI). Moreover, we noticed an elevation of neutrophil abundance in the AD brains. Conclusions We revealed the landscape of molecular perturbations at the cellular level for AD. These alterations highlight the putative roles of neutrophils in AD pathobiology.
... Their prevalence is rising and may double within the next 20 years (Tysnes and Storstein, 2017;Collaborators, 2019). Although the main damage underlying neurodegenerative disorders is in the brain, their onset and course is substantially affected by lifestyle, genetic predisposition, and somatic pathologies including infections associated with systemic inflammation (Holmes, 2013;Lim et al., 2015;Giridharan et al., 2019;Walker et al., 2019). Therefore, the hypothesis that COVID-19 infection can be a trigger or modifying factor of neurodegenerative diseases has been proposed (Verkhratsky et al., 2020). ...
Chapter
In humans, several respiratory viruses can have neurologic implications affecting both central and peripheral nervous system. Neurologic manifestations can be linked to viral neurotropism and/or indirect effects of the infection due to endothelitis with vascular damage and ischemia, hypercoagulation state with thrombosis and hemorrhages, systemic inflammatory response, autoimmune reactions, and other damages. Among these respiratory viruses, recent and huge attention has been given to the coronaviruses, especially the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic started in 2020. Besides the common respiratory symptoms and the lung tropism of SARS-CoV-2 (COVID-19), neurologic manifestations are not rare and often present in the severe forms of the infection. The most common acute and subacute symptoms and signs include headache, fatigue, myalgia, anosmia, ageusia, sleep disturbances, whereas clinical syndromes include mainly encephalopathy, ischemic stroke, seizures, and autoimmune peripheral neuropathies. Although the pathogenetic mechanisms of COVID-19 in the various acute neurologic manifestations are partially understood, little is known about long-term consequences of the infection. These consequences concern both the so-called long-COVID (characterized by the persistence of neurological manifestations after the resolution of the acute viral phase), and the onset of new neurological symptoms that may be linked to the previous infection.
... It has been reported that high levels of pro-inflammatory markers in the blood and other tissues are more often detected in older individuals [40] and that they may promote neurodegenerative events that can contribute to AD [41]. In the ARIC study, the relationship between plasma inflammatory markers during midlife and neurodegeneration 20 years later was investigated [42]. ...
Article
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Background Thioredoxin-80 (Trx80) is a cleavage product from the redox-active protein Thioredoxin-1 and has been previously described as a pro-inflammatory cytokine secreted by immune cells. Previous studies in our group reported that Trx80 levels are depleted in Alzheimer’s disease (AD) brains. However, no studies so far have investigated peripheral Trx80 levels in the context of AD pathology and whether could be associated with the main known AD risk factors and biomarkers. Methods Trx80 was measured in serum samples from participants from two different cohorts: the observational memory clinic biobank (GEDOC) ( N = 99) with AD CSF biomarker data was available and the population-based lifestyle multidomain intervention trial Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) ( N = 47), with neuroimaging data and blood markers of inflammation available. The GEDOC cohort consists of participants diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and AD, whereas the FINGER participants are older adults at-risk of dementia, but without substantial cognitive impairment. One-way ANOVA and multiple comparison tests were used to assess the levels of Trx80 between groups. Linear regression models were used to explore associations of Trx80 with cognition, AD CSF biomarkers (Aβ42, t-tau, p-tau and p-tau/t-tau ratio), inflammatory cytokines, and neuroimaging markers. Results In the GEDOC cohort, Trx80 was associated to p-tau/t-tau ratio in the MCI group. In the FINGER cohort, serum Trx80 levels correlated with lower hippocampal volume and higher pro-inflammatory cytokine levels. In both GEDOC and FINGER cohorts, ApoE4 carriers had significantly higher serum Trx80 levels compared to non-ApoE4 carriers. However, Trx80 levels in the brain were further decreased in AD patients with ApoE4 genotype. Conclusion We report that serum Trx80 levels are associated to AD disease stage as well as to several risk factors for AD such as age and ApoE4 genotype, which suggests that Trx80 could have potential as serum AD biomarker. Increased serum Trx80 and decreased brain Trx80 levels was particularly seen in ApoE4 carriers. Whether this could contribute to the mechanism by which ApoE4 show increased vulnerability to develop AD would need to be further investigated. Trial registration ClinicalTrials.gov NCT01041989 . Registered on 4 January 2010—retrospectively registered
... A growing number of studies have shown that patients with AD are accompanied by alterations in the peripheral immune system. 16,17 Therefore, we aimed to: (1) explore the relationship between air pollution and neuroinflammation represented by CSF sTREM2; (2) investigate the associations of air pollution exposure with systemic inflammatory markers, including high sensitivity Creactive protein (hsCRP) and peripheral immune cells; ...
Article
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Objectives: Ambient air pollution aggravates the process of Alzheimer's disease (AD) pathology. Currently, the exact inflammatory mechanisms underlying these links from clinical research remain largely unclear. Methods: This study included 1,131 cognitively intact individuals from the Chinese Alzheimer's Biomarker and LifestylE database with data provided on cerebrospinal fluid (CSF) AD biomarkers (amyloid beta-peptide 42 [Aβ42], total tau [t-tau], and phosphorylated tau [p-tau]), neuroinflammatory (CSF sTREM2), and systemic inflammatory markers (high sensitivity C-reactive protein and peripheral immune cells). The 2-year averaged levels of ambient fine particulate matter with diameter <2.5 μm (PM2.5 ), nitrogen dioxide (NO2 ), and ozone (O3 ) were estimated at each participant's residence. Multiple-adjusted models were approached to detect associations of air pollution with inflammatory markers and AD-related proteins. Results: Ambient 2-year averaged exposure of PM2.5 was associated with changes of neuroinflammatory markers, that is, CSF sTREM2 (β = -0.116, p = 0.0002). Similar results were found for O3 exposure among the elderly (β = -0.111, p = 0.0280) or urban population (β = -0.090, p = 0.0144). No significant evidence supported NO2 related to CSF sTREM2. For potentially causal associations with accumulated AD pathologies, the total effects of PM2.5 on CSF amyloid-related protein (CSF Aβ42 and p-tau/Aβ42) were partly mediated by CSF sTREM2, with proportions of 14.22% and 47.15%, respectively. Additional analyses found inverse associations between peripheral inflammatory markers with PM2.5 and NO2 , but a positive correlation with O3 . Interpretation: These findings demonstrated a strong link between PM2.5 exposure and microglial dysfunction. Furthermore, CSF sTREM2 as a key mediator modulated the influences of PM2.5 exposure on AD amyloid pathologies.
... Additionally, membrane PLs are a major source of lipid mediators that have a fundamental role in biological processes such as inflammation. Therefore, PL dyshomeostasis may also contribute to elevated systemic inflammation, which is characteristic of both AD and OSA [48,49]. Our results also linked several TG species to OSA severity in AD patients. ...
Article
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Background Obstructive sleep apnoea (OSA) is the most frequent form of sleep-disordered breathing in patients with Alzheimer’s disease (AD). Available evidence demonstrates that both conditions are independently associated with alterations in lipid metabolism. However, it is unknown whether the expression of lipids is different between AD patients with and without severe OSA. In this context, we examined the plasma lipidome of patients with suspected OSA, aiming to identify potential diagnostic biomarkers and to provide insights into the pathophysiological mechanisms underlying the disease. Methods The study included 103 consecutive patients from the memory unit of our institution with a diagnosis of AD. The individuals were subjected to overnight polysomnography (PSG) to diagnose severe OSA (apnoea-hypopnea index ≥30/h), and blood was collected the following morning. Untargeted plasma lipidomic profiling was performed using liquid chromatography coupled with mass spectrometry. Results We identified a subset of 44 lipids (mainly phospholipids and glycerolipids) that were expressed differently between patients with AD and severe and nonsevere OSA. Among the lipids in this profile, 30 were significantly correlated with specific PSG measures of OSA severity related to sleep fragmentation and hypoxemia. Machine learning analyses revealed a 4-lipid signature (phosphatidylcholine PC(35:4), cis-8,11,14,17-eicosatetraenoic acid and two oxidized triglycerides (OxTG(58:5) and OxTG(62:12)) that provided an accuracy (95% CI) of 0.78 (0.69–0.86) in the detection of OSA. These same lipids improved the predictive power of the STOP-Bang questionnaire in terms of the area under the curve (AUC) from 0.61 (0.50–0.74) to 0.80 (0.70–0.90). Conclusion Our results show a plasma lipidomic fingerprint that allows the identification of patients with AD and severe OSA, allowing the personalized management of these individuals. The findings suggest that oxidative stress and inflammation are potential prominent mechanisms underlying the association between OSA and AD.
... Systemic inflammation may contribute to the onset of AD. Multiple epidemiological and animal studies have provided evidence that systemic inflammatory conditions caused by peripheral infections may be associated with a greater risk of AD and can accelerate disease progression [18,19]. In APPswe transgenic mice, the systemic administration of an endotoxin lipopolysaccharide (LPS) led to enhanced APP expression and increased intracellular accumulation of Aβ [20]. ...
Article
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Cytosolic phospholipase A2 (cPLA2) is an enzyme regulating membrane phospholipid homeostasis and the release of arachidonic acid utilized in inflammatory responses. It represents an attractive target for the treatment of Alzheimer’s disease (AD). Previously, we showed that lipopolysaccharide (LPS)-induced systemic inflammation caused abnormal lipid metabolism in the brain of a transgenic AD mouse model (APdE9), which might be associated with potential changes in cPLA2 activity. Here, we investigated changes in cPLA2 expression and activity, as well as the molecular mechanisms underlying these alterations due to chronic LPS administration in the cerebral cortex of female APdE9 mice as compared to saline- and LPS-treated female wild-type mice and saline-treated APdE9 mice. The study revealed the significant effects of genotype LPS treatment on cortical cPLA2 protein expression and activity in APdE9 mice. LPS treatment resulted in nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) activation in the cortex of APdE9 mice. The gene expressions of inflammation markers Il1b and Tnfa were significantly elevated in the cortex of both APdE9 groups compared to the wild-type groups. The study provides evidence of the elevated expression and activity of cPLA2 in the brain cortex of APdE9 mice after chronic LPS treatment, which could be associated with NFkB activation.
... Changes in the levels of circulatory cytokines are often observed during AD (Walker et al., 2019) and metabolic disease (Guarner and Rubio-Ruiz, 2015) and higher levels of IL-10 were observed in the circulation of the Control mice compared to the Probiotic mice. As previously mentioned, IL-10 is generally considered to be anti-inflammatory and it is plausible that higher levels in the Control group form part of the host response to the overtly inflammatory systemic environment that was absent in the Probiotic mice. ...
Article
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Brain degenerative disorders such as Alzheimer’s disease (AD) can be exacerbated by aberrant metabolism. Supplementation with probiotic bacteria is emerging as a promising preventative strategy for both neurodegeneration and metabolic syndrome. In this study, we assess the impact of the Lab4b probiotic consortium on (i) cognitive and pathological markers of AD progression and (ii) metabolic status in 3xTg-AD mice subjected to metabolic challenge with a high fat diet. The group receiving the probiotic performed better in the novel object recognition test and displayed higher hippocampal neuronal spine density than the control group at the end of the 12 weeks intervention period. These changes were accompanied by differences in localised (brain) and systemic anti-inflammatory responses that favoured the Probiotic group together with the prevention of diet induced weight gain and hypercholesterolaemia and the modulation of liver function. Compositional differences between the faecal microbiotas of the study groups included a lower Firmicutes:Bacteroidetes ratio and less numbers of viable yeast in the Probiotic group compared to the Control. The results illustrate the potential of the Lab4b probiotic as a neuroprotective agent and encourage further studies with human participants.
... Furthermore, increased levels of oxidative stress in the brain over cellular antioxidant defenses can damage cellular structures and increase accumulation of beta-amyloid and neurofibrillary tangles. Increased oxidative stress and systemic inflammation may occur as a result of events such as infection, chronic disease, physical and psychological stress, and cellular aging (Walker et al. 2019;Buccellato et al. 2021). ...
Article
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Breakthrough infections have been reported in fully vaccinated persons. Furthermore, rebound symptoms have been reported following the new FDA granted emergency use to combat SARS-CoV-2. Glycyrrhizin (GR) and boswellic acids (BAs) combination has been shown to have highly successful actions against COVID-19 in our recent clinical trial. However, the study is limited by the small sample size, and therefore, the aim of this article is to comprehensively evaluate recent evidence on the efficacy of GR and BAs in preventing the development of COVID-19 in patients with mild and moderate infections and in preventing post-COVID-19 cognitive impairment, which is the most important symptom after recovery from Covid-19 disease. We have reviewed and discussed information published since the outbreak of the COVID-19 pandemic until July 2022 on preclinical (in vivo, in vivo and bioinformatics) and clinical studies related to the antiviral, anti-inflammatory and immunomodulatory activity of Gr and BAs. Sixteen studies were performed to determine the efficacy of GR against SARS-CoV-2. Ten studies were used primarily for in vitro and in vivo assays and six used molecular docking studies. However, the antiviral activity of BAs against SARS-CoV-2 was determined in only five studies using molecular modeling and bioinformatics. All these studies confirmed that GR n and BAs have strong antiviral activity and can be used as a therapeutic agent for COVID-19 and as a protective agent against SARS-CoV-2. They may act by inhibiting the main protease SARS-CoV-2 (Mpro) responsible for replication and blocking spike protein-mediated cell entry. Only seven rigorously designed clinical trials regarding the usefulness of GR, BAs or their combinations in the treatment of COVID-19 have been published as of July 2022. Although there is no clinical study regarding the treatment of cognitive impairment after COVID-19 that has been published so far, several preclinical and clinical studies have demonstrated the potential effect of GR and BAs in the prevention and treatment of cognitive impairment by inhibiting the activity of several molecules that activate inflammatory signaling pathway. In conclusion, the findings of our study documented the beneficial use of GR and BAs to treat SARS-CoV-2 and its variants and prevent post-COVID cognitive impairment. However, it warrants further studies with a larger randomized sample size to ensure that the studies have sufficient evidence of benefits against COVID-19 and post-COVID-19 symptoms.
... Elevated levels of IL-6 are also found in serum and brain tissue of people with AD (24). Systemic inflammation in AD is also argued to induce proinflammatory states of microglia and astrocytic phenotypes, which stimulate tau hyperphosphorylation, Aβ oligomerization, component activation, and the breakdown of neurotransmitters into potentially toxic metabolites (25). ...
Article
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Alzheimer's disease (AD) is a global public health priority as with aging populations, its prevalence is expected to rise even further in the future. The brain and gut are in close communication through immunological, nervous and hormonal routes, and therefore, probiotics are examined as an option to influence AD hallmarks, such as plaques, tangles, and low grade inflammation. This study aimed to provide an overview of the available animal evidence on the effect of different probiotics on gut microbiota composition, short chain fatty acids (SCFAs), inflammatory markers, Amyloid-β (Aβ), and cognitive functioning in AD animal models. A systematic literature search was performed in PubMed, SCOPUS, and APA PsychInfo. Articles were included up to May 2021. Inclusion criteria included a controlled animal study on probiotic supplementation and at least one of the abovementioned outcome variables. Of the eighteen studies, most were conducted in AD male mice models (n = 9). Probiotics of the genera Lactobacillus and Bifidobacterium were used most frequently. Probiotic administration increased species richness and/or bacterial richness in the gut microbiota, increased SCFAs levels, reduced inflammatory markers, and improved cognitive functioning in AD models in multiple studies. The effect of probiotic administration on Aβ remains ambiguous. B. longum (NK46), C. butyricum, and the mixture SLAB51 are the most promising probiotics, as positive improvements were found on almost all outcomes. The results of this animal review underline the potential of probiotic therapy as a treatment option in AD.
... Until recently, it was believed that neuroinflammation may be a central mechanism driving amyloid  (A pathology and progression. Genetic studies along with results from epidemiological and translational research indicate that inflammation outside of the central nervous system or systemic inflammation is another detrimental factor that can contribute to AD initiation and progression [3,4]. In peripheral inflammation, circulating phagocytes (granulocytes and monocytes) are key players [5]. ...
Article
Aim. The purpose of the study was to evaluate manifestations of systemic inflammation in rats with Alzheimer disease (AD) induced by injections of A?1-40 and A?25-35 by the assessment of functional polarization of circulating phagocytes. Methods. AD was induced by intracerebral injections of A?1–40 and A?25–35 Wistar male rats. Intact and sham-operated animals were used as a control. AD development was affirmed by the assessment of cognitive impairment in behavioral tests (‘Open field’ test, apomorphine test, Barnes maze test), as well as by the level of death of dopaminergic neurons. The functional polarization of circulating phagocytes was designated by phagocytic activity, oxidative metabolism, and the expression of phenotypic markers CD80 and CD206, which were examined by flow cytometry. Results. Circulating phagocytes from rats with A?1-40-induced AD were characterized by increased fraction of phagocytizing monocytes with decreased endocytic activity, moderately up-regulated granulocyte ROS generation along with temperate increase of CD86+ mononuclear phagocyte fraction and high level of CD206 expression. Two widely accepted indices of systemic inflammation: NLR and SII were higher in these animals than those in control rats by 6,5 and 7,5 times respectively. In rats with A?25-35-induced disease, significantly increased granulocyte ROS generation was registered. NLR and SII values in these animals were slightly higher than those in control rats. Conclusion. Therefore, A?1-40 AD model reproduces disease-associated systemic inflammation at the greater extent than A?25-35-induced pathology, and is more appropriate for the study of inflammation in the disease pathophysiology.
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Objective: To investigate vagotomy, the severance of the vagus nerve, and its association with mental disorders, as gut-brain communication partly mediated by the vagus nerve have been suggested as a risk factor. Methods: Nationwide population-based Danish register study of all individuals alive and living in Denmark during the study period 1977-2016 and who had a hospital contact for ulcer with or without vagotomy. Follow-up was until any diagnosis of mental disorders requiring hospital contact, emigration, death, or end of follow-up on December 31, 2016, whichever came first. Data were analysed using survival analysis and adjusted for sex, age, calendar year, ulcer type and Charlson comorbidity index score. Results: During the study period, 113,086 individuals had a hospital contact for ulcer. Of these, 5,408 were exposed to vagotomy where 375 (6.9%) subsequently developed a mental disorder. Vagotomy overall was not associated with mental disorders (HR: 1.10; 95%CI: 0.99-1.23), compared to individuals with ulcer not exposed to vagotomy. However, truncal vagotomy was associated with an increased HR of 1.22 (95%CI: 1.06-1.41) for mental disorders, whereas highly selective vagotomy was not associated with mental disorders (HR: 0.98; 95%CI: 0.84-1.15). Truncal vagotomy was also associated with higher risk of mental disorders when compared to highly selective vagotomy (p=0.034). Conclusions: Overall, vagotomy did not increase the risk of mental disorders; however, truncal vagotomy specifically was associated with a small risk increase in mental disorders, whereas no association was found for highly selective vagotomy. Thus, the vagus nerve does not seem to have a major impact on the development of mental disorders.
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Alzheimer’s disease (AD) and other dementias are now the seventh leading cause of death in the world and are projected to affect 115.4 million people by 2050. Delaying the onset of AD by just five years is estimated to reduce the cost and prevalence of the disease by half. There is no cure for AD nor any drug therapies to halt its progression once the disease begins. Lifestyle choices including diet are being seen as a viable complementary therapy to reduce cognitive decline, the hallmark of AD. Mediterranean, DASH (Dietary Approaches to Stop Hypertension), and MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diets have biological mechanisms supporting their potential neuroprotective benefits, but the findings of study outcomes about these benefits have been inconsistent. This paper analyzed five Randomized Clinical Trials (RCTs) (from 2000 to 2021) and 27 observational studies (from 2010 to 2021) focused on the link between cognitive health and the Mediterranean/DASH/MIND diets to identify gaps and challenges that could lead to inconsistent results. These include a lack of accuracy in assessing food intake, multiple dietary pattern scoring systems, a shifting metric among studies focused on the Mediterranean diet, a lack of standards in the tools used to assess cognitive decline, and studies that were underpowered or had follow-up periods too short to detect cognitive change. Insights from these gaps and challenges are summarized in recommendations for future RCTs, including both pragmatic and explanatory RCTs.
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Integrated microfluidic cellular phenotyping platforms provide a promising means of studying a variety of inflammatory diseases mediated by cell‐secreted cytokines. However, immunosensors integrated in previous microfluidic platforms lack the sensitivity to detect small signals in the cellular secretion of proinflammatory cytokines with high precision. This limitation prohibits researchers from studying cells secreting cytokines at low abundance or existing at a small population. Herein, the authors present an integrated platform named the “digital Phenoplate (dPP),” which integrates digital immunosensors into a microfluidic chip with on‐chip cell assay chambers, and demonstrates ultrasensitive cellular cytokine secretory profile measurement. The integrated sensors yield a limit of detection as small as 0.25 pg mL−1 for mouse tumor necrosis factor alpha (TNF‐α). Each on‐chip cell assay chamber confines cells whose population ranges from ≈20 to 600 in arrayed single‐cell trapping microwells. Together, these microfluidic features of the dPP simultaneously permit precise counting and image‐based cytometry of individual cells while performing parallel measurements of TNF‐α released from rare cells under multiple stimulant conditions for multiple samples. The dPP platform is broadly applicable to the characterization of cellular phenotypes demanding high precision and high throughput. This study develops a cellular phenotyping platform for cell trapping/culture, digital‐molecular‐counting immunosensing, and image‐based cytometry on a single microfluidic chip. The platform enables ultrasensitive cytokine detection and multiparametric phenotyping of multiple rare cell samples. It is extensively applied on studying primary microglia's functional phenotypic differences between amyloid‐expressing Alzheimer's disease model mice and wild‐type mice.
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Increased life expectancy in combination with modern life style and high prevalence of obesity are important risk factors for development of neurodegenerative diseases. Neuroinflammation is a feature of neurodegenerative diseases, and microglia, the innate immune cells of the brain, are central players in it. The present review discusses the effects of obesity, chronic peripheral inflammation and obesity-associated metabolic and endocrine perturbations, including insulin resistance, dyslipidemia and increased glucocorticoid levels, on microglial function.
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Background: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA). Objective: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults. Methods: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education. Results: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up. Conclusion: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.
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The functions of platelets are broad. Platelets function in hemostasis and thrombosis, inflammation and immune responses, vascular regulation, and host defense against invading pathogens, among others. These actions are achieved through the release of a wide set of coagulative, vascular, inflammatory, and other factors as well as diverse cell surface receptors involved in the same activities. As active participants in these physiological processes, platelets become involved in signaling pathways and pathological reactions that contribute to diseases that are defined by inflammation (including by pathogen-derived stimuli), vascular dysfunction, and coagulation. These diseases include Alzheimer's and Parkinson's disease, the two most common neurodegenerative diseases. Despite their unique pathological and clinical features, significant shared pathological processes exist between these two conditions, particularly relating to a central inflammatory mechanism involving both neuroinflammation and inflammation in the systemic environment, but also neurovascular dysfunction and coagulopathy, processes which also share initiation factors and receptors. This triad of dysfunction-(neuro)inflammation, neurovascular dysfunction, and hypercoagulation-illustrates the important roles platelets play in neuropathology. Although some mechanisms are understudied in Alzheimer's and Parkinson's disease, a strong case can be made for the relevance of platelets in neurodegeneration-related processes.
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It has long been recognized that there exists a unique interaction between the peripheral immune system and the brain, an interaction that is increasingly proving to be critical in the normal physiology of the brain and the pathogenesis of neurodegenerative disorders. One such peripheral factor that alters brain function is systemic inflammation. Occurring mostly in response to infections, systemic inflammation induces behavioral deficits, alters cognitive function, and has been hypothesized to contribute significantly to the pathogenesis of dementia. With increasing evidence of the crucial role of inflammation in Alzheimer’s disease (AD), coupled with the numerous failed therapeutic attempts in targeting beta-amyloid (Aβ) in AD, the infection-induced systemic inflammation hypothesis is rapidly gaining popularity as a key player in the development of dementia and other neurodegenerative disorders. This chapter summarizes other postulates, and examines them against the infection-induced systemic inflammation hypothesis, discussing their roles in the pathogenesis of neurodegeneration. We describe the effect of infection on both the chronic and acute cognitive changes in dementia, and the implications of various systemic inflammatory markers in the development of dementia. There is a deterioration of both cognitive ability and behavioral functions in demented patients who suffer from infections with a systemic inflammatory component. This chapter delves into the effects of systemic inflammation on the central nervous system (CNS) including activation of microglial and astrocytic cells, as well as the effects of infection on integrity of the blood–brain barrier. We also discuss conventional and novel pharmacological agents and phytochemicals that are used in targeting infection-induced systemic inflammatory mediation in the management of dementia.
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Alzheimer’s disease (AD) is the most frequent cause of dementia due to neurodegeneration. It is stated that the most important risk factor for the late onset AD development is age. AD develops during decades and appears most of the time after 65 years of age. Even though its incidence is increasing with age but not all the centenarians are suffering from AD. The most important underlying age-related factor is immunosenescence/inflammaging. Indeed, aging is associated with immune changes which are thought to be the most prevalent cause of the age-related chronic inflammatory diseases. However, it is now postulated that the changes occurring with aging in the immune system may not be only detrimental but also adaptive. Therefore, in this review we will describe whether and how immunosenescence/inflammaging may contribute to the development of AD. We will also examine whether this can lead to novel treatment approaches different form the current.KeywordsAlzheimer’s disease (AD)Mild cognitive impairment (MCI)ImmunosenescenceInflammaging neuroinflammationMonocytesMacrophagesPhagocytosisFree radicalsCytokinesSignaling
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Background: Late-onset Alzheimer's disease (LOAD) is associated with many environmental and genetic factors. The effect of systemic inflammation on the pathogenesis of neurodegenerative diseases such as AD has been strongly suggested. T helper cells (Th) are one of the important components of the immune system and can easily infiltrate the brain in pathological conditions. The development of each Th-subset depends on the production of unique cytokines and their main regulator. Objective: This study aimed to compare the mRNA levels of Th-related genes derived from peripheral blood mononuclear cells of LOAD patients with control. Also, the identification of the most important Th1/Th2 genes and downstream pathways that may be involved in the pathogenesis of AD was followed by computational approaches. Methods: This study invloved 30 patients with LOAD and 30 non-demented controls. The relative expression of T-cell cytokines (IFN-γ, TNF-α, IL-4, and IL-5) and transcription factors (T-bet and GATA-3) were assessed using real-time PCR. Additionally, protein-protein interaction (PPI) was investigated by gene network construction. Results: A significant decrease at T-bet, IFN-γ, TNF-α, and GATA-3 mRNA levels was detected in the LOAD group, compared to the controls. However, there was no significant difference in IL-4 or IL-5 mRNA levels. Network analysis revealed a list of the highly connected protein (hubs) related to mitogen-activated protein kinase (MAPK) signaling and Th17 cell differentiation pathways. Conclusion: The findings point to a molecular dysregulation in Th-related genes, which can promising in the early diagnosis or targeted interventions of AD. Furthermore, the PPI analysis showed that upstream off-target stimulation may involve MAPK cascade activation and Th17 axis induction.
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Peripheral inflammation is elevated in older Black adults, an elevation which prior work has suggested may be due to chronic stress associated with systemic racism and related adverse cardiovascular health conditions. Inflammation is also involved in the pathogenic processes of dementia; however, limited (and mixed) results exist concerning inflammation and cognitive decline in Black adults. We characterized patterns of inflammation and their role in cognitive decline in 280 older Black adults (age=72.99±6.00 years; 69.6% female) from the Minority Aging Research Study (MARS) who were without dementia at baseline and followed between 2 and 15 years (mean=9 years). Participants completed a blood draw at baseline and annual cognitive evaluations. Serum was assayed for 9 peripheral inflammatory markers; 19 neuropsychological test scores were used to create indices of global cognition and five cognitive domains. Principal component analysis with varimax rotation characterized patterns of inflammation with factor loadings >0.6 per component contributing to two composite scores representing acute/upstream and chronic/downstream inflammation. These composites were used as separate predictors in linear mixed regression models to determine associations with level and change in cognition adjusting for relevant covariates. Higher baseline upstream/acute inflammation associated with lower baseline semantic memory (p=.040) and perceptual speed (p=.046); it was not related to cognitive decline. By contrast, higher baseline downstream/chronic inflammation associated with faster declines in global cognition (p=.010), episodic (p=.027) and working memory (p=.006); it was not related to baseline cognition. For older Black adults, chronic, but not acute, inflammation may be a risk factor for changes in cognition.
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Gestational maternal immune activation (MIA) in mice induces persistent brain microglial activation and a range of neuropathologies in the adult offspring. Although long-term phenotypes are well documented, how MIA in utero leads to persistent brain inflammation is not well understood. Here, we found that offspring of mothers treated with polyriboinosinic–polyribocytidylic acid [poly(I:C)] to induce MIA at gestational day 13 exhibit blood–brain barrier (BBB) dysfunction throughout life. Live MRI in utero revealed fetal BBB hyperpermeability 2 d after MIA. Decreased pericyte–endothelium coupling in cerebral blood vessels and increased microglial activation were found in fetal and 1- and 6-mo-old offspring brains. The long-lasting disruptions result from abnormal prenatal BBB formation, driven by increased proliferation of cyclooxygenase-2 (COX2; Ptgs2)-expressing microglia in fetal brain parenchyma and perivascular spaces. Targeted deletion of the Ptgs2 gene in fetal myeloid cells or treatment with the inhibitor celecoxib 24 h after immune activation prevented microglial proliferation and disruption of BBB formation and function, showing that prenatal COX2 activation is a causal pathway of MIA effects. Thus, gestational MIA disrupts fetal BBB formation, inducing persistent BBB dysfunction, which promotes microglial overactivation and behavioral alterations across the offspring life span. Taken together, the data suggest that gestational MIA disruption of BBB formation could be an etiological contributor to neuropsychiatric disorders.
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Amyloid deposits and hyperphosphorylation of the tau protein are still believed to be the two main causes of Alzheimer’s disease. However, newer studies show the beneficial (including antiradical and antimicrobial) effects of amyloid at physiological concentrations. Therefore, this study aimed to investigate the impact of three amyloid fragments – 25–35, 1–40, and 1–42 at concentrations close to physiological levels on the oxidative stress induced by the administration of lipopolysaccharide (LPS) or co-culturing with microglia cells. Differentiated SH-SY5Y cells were used, constituting a model of neuronal cells that were preincubated with LPS or supernatant collected from THP-1 cell culture. The cells were treated with amyloid-β fragments at concentrations of 0.001, 0.1, and 1.0 µM, and then biological assays were carried out. The results of the study support the antioxidant properties of Aβ, which may protect neurons from the damaging effects of neuroinflammation. All tested amyloid-β fragments reduced oxidative stress and increased the levels of enzymatic stress parameters – the activity of SOD, GPx and catalase. In addition, the administration of amyloid-β at low physiological concentrations also increased reduced glutathione (GSH) levels and the ratio between reduced and oxidized glutathione (GSH/GSSG), which is considered a good indicator of maintaining cellular redox balance. Furthermore, a stronger antioxidant effect of 1–40 fragment was observed, occurring in a wider range of concentrations, compared to the other tested fragments 25–35 and 1–42.
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Background: Type 2 diabetes (T2D) is an established risk factor for dementia. However, it remains unclear whether the presence of comorbidities could further increase dementia risk in diabetes patients. Objectives: To examine the associations between cardiovascular and non-cardiovascular comorbidities and dementia risk in T2D patients. Design: Population-based cohort study. Setting: The UK Clinical Practice Research Datalink (CPRD). Participants: 489,205 T2D patients aged over 50 years in the UK CPRD. Measurements: Major cardiovascular and non-cardiovascular comorbidities were extracted as time-varying exposure variables. The outcome event was dementia incidence based on dementia diagnosis or dementia-specific drug prescription. Results: During a median of six years follow-up, 33,773 (6.9%) incident dementia cases were observed. Time-varying Cox regressions showed T2D patients with stroke, peripheral vascular disease, atrial fibrillation, heart failure or hypertension were at higher risk of dementia compared to those without such comorbidities (HR [95% CI] = 1.64 [1.59-1.68], 1.37 [1.34-1.41], 1.26 [1.22-1.30], 1.15 [1.11-1.20] or 1.10 [1.03-1.18], respectively). Presence of chronic obstructive pulmonary disease or chronic kidney disease was also associated with increased dementia risk (HR [95% CI] = 1.05 [1.01-1.10] or 1.11 [1.07-1.14]). Conclusions: A range of cardiovascular and non-cardiovascular comorbidities were associated with further increases of dementia risk in T2D patients. Prevention and effective management of these comorbidities may play a significant role in maintaining cognitive health in T2D patients.
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Co-morbidity and systemic inflammation as drivers of cognitive decline: new experimental models adopting a broader paradigm in dementia research Abstract Dementia prevalence increases with age and Alzheimer's disease (AD) accounts for up to 75% of cases. However, significant variability and overlap exists in the extent of amyloid-β and Tau pathology in AD and non-demented populations and it is clear that other factors must influence progression of cognitive decline, perhaps independent of effects on amyloid pathology. Coupled with the failure of amyloid-clearing strategies to provide benefits for AD patients, it seems necessary to broaden the paradigm in dementia research beyond amyloid deposition and clearance. Evidence has emerged from alternative animal model approaches as well as clinical and population epidemiological studies that co-morbidities contribute significantly to neurodegeneration/cognitive decline and systemic inflammation has been a strong common theme in these approaches. We hypothesise, and discuss in this review, that a disproportionate inflammatory response to infection, injury or chronic peripheral disease is a key determinant of cognitive decline. We propose that detailed study of alternative models, which encompass acute and chronic systemic inflammatory co-morbidities, is an important priority for the field and we examine the cognitive consequences of several of these alternative experimental approaches. Experimental models of severe sepsis in normal animals or moderate acute systemic inflammation in animals with existing neurodegenerative pathology have uncovered roles for inflammatory mediators interleukin-1β, tumour necrosis factor-α, inducible nitric oxide synthase, complement, prostaglandins and NADPH oxidase in inflammation-induced cognitive dysfunction and neuronal death. Moreover, microglia are primed by existing neurodegenerative pathology to produce exaggerated responses to subsequent stimulation with bacterial lipopolysaccharide or other inflammatory stimuli and these insults drive acute dysfunction and negatively affect disease trajectory. Chronic co-morbidities, such as arthritis, atherosclerosis, obesity and diabetes, are risk factors for subsequent dementia and those with high inflammatory status are particularly at risk. Models of chronic co-morbidities, and indeed low grade systemic inflammation in the absence of specific pathology, indicate that interleukin-1β, tumour necrosis factor-α and other inflammatory mediators drive insulin resistance, hypothalamic dysfunction, impaired neurogenesis and cognitive function and impact on functional decline. Detailed study of these pathways will uncover important mechanisms of peripheral inflammation-driven cognitive decline and are already driving clinical initiatives to mitigate AD progression through minimising systemic inflammation.
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The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper-or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.
Article
Objective: To examine the association between systemic inflammation measured during midlife and 20-year cognitive decline. Methods: Within the Atherosclerosis Risk in Communities cohort study, inflammatory biomarkers were measured during middle adulthood. We created an inflammation composite score using 4 blood biomarkers measured at visit 1 (fibrinogen, white blood cell count, von Willebrand factor, and factor VIII); we measured C-reactive protein (CRP) at visit 2. Cognition was assessed over 3 visits spanning 20 years using measures of memory, executive function, and language. Results: A total of 12,336 participants (baseline age 56.8 [5.7], 21% black, 56% women) were included. After adjusting for demographic variables, vascular risk factors, and comorbidities, each standard deviation (SD) increase in midlife inflammation composite score was associated with an additional 20-year decline of -0.035 SD (95% confidence interval: -0.062 to -0.007) on the cognitive composite score. We found a similar association between each SD increase in midlife CRP level and additional 20-year cognitive decline (-0.038 SD, 95% confidence interval: -0.057 to -0.019). Participants with a midlife inflammation composite score in the top quartile had a 7.8% steeper cognitive decline, compared to participants in the lowest quartile; CRP in the top quartile was associated with an 11.6% steeper cognitive decline. In cognitive domain-specific analyses, elevated midlife inflammatory markers were most consistently associated with declines in memory. Results were similar after adjusting for attrition using inverse probability weighting. Conclusions: Our findings highlight what may be an early pathogenic role for systemic inflammation as a driver of cognitive decline in the decades leading up to older adulthood.
Article
We examined whether the pattern of middle- to late-life systemic inflammation was associated with white matter (WM) structural abnormalities in older adults. A total of 1532 participants (age = 76.5; standard deviations = 5.4) underwent 3T brain magnetic resonance imaging to quantify white matter hyperintensity volume and whole-brain WM microstructural integrity (fractional anisotropy, mean diffusivity). High-sensitivity C-reactive protein (CRP), a marker of systemic inflammation, was measured at 3 visits (21 and 14 years before, and concurrent with, neuroimaging). Participants were categorized into 1 of 6 groups based on their 21-year pattern of low (<3 mg/L) versus elevated (≥3 mg/L) CRP. Compared to the group with low CRP at all 3 visits, the group that transitioned from low to elevated CRP during midlife demonstrated greatest white matter hyperintensity volume and poorest WM microstructural integrity, after adjusting for demographic variables and cardiovascular risk factors. Participants with high CRP at all visits also demonstrated greater WM structural abnormalities, but only after accounting for differential attrition. These results suggest that increasing and persistent inflammation in the decades spanning middle-to late-life may promote WM disease in older adults.
Article
Objective: To clarify the temporal relationship between systemic inflammation and neurodegeneration, we examined whether a higher level of circulating inflammatory markers during midlife was associated with smaller brain volumes in late life using a large biracial prospective cohort study. Methods: Plasma levels of systemic inflammatory markers (fibrinogen, albumin, white blood cell count, von Willebrand factor, and Factor VIII) were assessed at baseline in 1,633 participants (mean age 53 [5] years, 60% female, 27% African American) enrolled in the Atherosclerosis Risk in Communities Study. Using all 5 inflammatory markers, an inflammation composite score was created for each participant. We assessed episodic memory and regional brain volumes, using 3T MRI, 24 years later. Results: Each SD increase in midlife inflammation composite score was associated with 1,788 mm(3) greater ventricular (p = 0.013), 110 mm(3) smaller hippocampal (p = 0.013), 519 mm(3) smaller occipital (p = 0.009), and 532 mm(3) smaller Alzheimer disease signature region (p = 0.008) volumes, and reduced episodic memory (p = 0.046) 24 years later. Compared to participants with no elevated (4th quartile) midlife inflammatory markers, participants with elevations in 3 or more markers had, on average, 5% smaller hippocampal and Alzheimer disease signature region volumes. The association between midlife inflammation and late-life brain volume was modified by age and race, whereby younger participants and white participants with higher levels of systemic inflammation during midlife were more likely to show reduced brain volumes subsequently. Conclusions: Our prospective findings provide evidence for what may be an early contributory role of systemic inflammation in neurodegeneration and cognitive aging.