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The relationship between amyloid-β (Aβ), mitochondrial electron transport chain (ETC), and superoxide (O2 −∙) formation. As electrons are transferred through complexes I, III, and IV, protons are pumped into the inner membrane space, generating an electrochemical gradient. The energy stored is used to generate ATP via complex V (ATP synthase). Damage to components of the ETC can lead to a stalling of reduced intermediates which increases the probability of electrons slipping and reducing O2 to form superoxide. Aβ has been shown to directly inhibit complex IV which would lead to bioenergetic impairment and increased formation of reactive oxygen species.
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Hypometabolism is a hallmark of Alzheimer's disease (AD) and implicates a mitochondrial role in the neuropathology associated with AD. Mitochondrial amyloid-beta (Aβ) accumulation precedes extracellular Aβ deposition. In addition to increasing oxidative stress, Aβ has been shown to directly inhibit mitochondrial enzymes. Inhibition of mitochondrial...
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... decreased metabolism and synaptic loss have been shown to overlap in the frontal and middle temporal gyri [14][15][16][17]. Mitochondria sustain the activity of neurons by produc- ing ATP via the electron transport system (ETC) (Figure 1). Complex I (NADH dehydrogenase) catalyzes the transfer of two electrons from NADH to coenzyme Q [18]. ...Citations
... TPK1 hyperphosphorylates tau [59] and inhibits PDH [60], which inhibits acetyl-CoA and citrate in mitochondria resulting in a decrease of ACh synthesis and causes memory and cognition impairment [15]. A interacts with mitochondrial cyclophilin D and causes cell death [61]. Acetyl-CoA is the direct energy source for the brain cells [16]. ...
Citrate synthase is a key mitochondrial enzyme that utilizes acetyl-CoA and oxaloacetate to form citrate in the mitochondrial membrane, which participates in energy production in the TCA cycle and linked to the electron transport chain. Citrate transports through a citrate malate pump and synthesizes acetyl-CoA and acetylcholine (ACh) in neuronal cytoplasm. In a mature brain, acetyl-CoA is mainly utilized for ACh synthesis and is responsible for memory and cognition. Studies have shown low citrate synthase in different regions of brain in Alzheimer’s disease (AD) patients, which reduces mitochondrial citrate, cellular bioenergetics, neurocytoplasmic citrate, acetyl-CoA, and ACh synthesis. Reduced citrate mediated low energy and favors amyloid-β (Aβ) aggregation. Citrate inhibits Aβ25–35 and Aβ1–40 aggregation in vitro. Hence, citrate can be a better therapeutic option for AD by improving cellular energy and ACh synthesis, and inhibiting Aβ aggregation, which prevents tau hyperphosphorylation and glycogen synthase kinase-3 beta. Therefore, we need to study if citrate reverses Aβ deposition by balancing mitochondrial energy pathway and neurocytoplasmic ACh production. Furthermore, in AD’s silent phase pathophysiology, when neuronal cells are highly active, they shift ATP utilization from oxidative phosphorylation to glycolysis and prevent excessive generation of hydrogen peroxide and reactive oxygen species (oxidative stress) as neuroprotective action, which upregulates glucose transporter-3 (GLUT3) and pyruvate dehydrogenase kinase-3 (PDK3). PDK3 inhibits pyruvate dehydrogenase, which decreases mitochondrial-acetyl-CoA, citrate, and cellular bioenergetics, and decreases neurocytoplasmic citrate, acetyl-CoA, and ACh formation, thus initiating AD pathophysiology. Therefore, GLUT3 and PDK3 can be biomarkers for silent phase of AD.
... Pathological study of patient brain suffering from AD exhibited the aggregation of autophagosomes as well as prelysosomal autophagic vacuoles that further caused the accumulation of Aβ plaques (Nixon et al., 2005;Yu et al., 2005). It has been demonstrated that a deficit in the respiratory chain in response to mitochondrial structural change promotes the overgeneration of ROS and reduction in ATP concentration which results in lack of energy, neuronal death and NDs (Readnower et al., 2011). Moreover, mitochondrial dysfunction is induced by Aβ toxicity via modulating the mitochondrial fission and fusion process. ...
Most polyphenols can cross blood-brain barrier, therefore, they are widely utilized in the treatment of various neurodegenerative diseases (ND). Resveratrol, a natural polyphenol contained in blueberry, grapes, mulberry, etc., is well documented to exhibit potent neuroprotective activity against different ND by mitochondria modulation approach. Mitochondrial function impairment is the most common etiology and pathological process in various neurodegenerative disorders, viz. Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. Nowadays these ND associated with mitochondrial dysfunction have become a major threat to public health as well as health care systems in terms of financial burden. Currently available therapies for ND are limited to symptomatic cures and have inevitable toxic effects. Therefore, there is a strict requirement for a safe and highly effective drug treatment developed from natural compounds. The current review provides updated information about the potential of resveratrol to target mitochondria in the treatment of ND.
... Currently, TSPO is the primary target for PET and SPECT in vivo neuroinflammatory imaging to monitor the inflammatory state in the brain (Tournier et al., 2020;López-Picón et al., 2022). According to one of the hypotheses of AD pathogenesis, mitochondrial dysfunction occurs in the early stages, and thus, maintaining mitochondrial function may be a therapeutic strategy for AD (Readnower et al., 2011;Eckert et al., 2012;. Kim et al. identified novel TSPO ligands that can restore Aβ-induced mitochondrial dysfunction and improve cognitive impairment in mouse models with AD . ...
Alzheimer's disease (AD), the most common neurodegenerative disease, remains unclear in terms of its underlying causative genes and effective therapeutic approaches. Meanwhile, abnormalities in iron metabolism have been demonstrated in patients and mouse models with AD. Therefore, this study sought to find hub genes based on iron metabolism that can influence the diagnosis and treatment of AD. First, gene expression profiles were downloaded from the GEO database, including non-demented (ND) controls and AD samples. Fourteen iron metabolism-related gene sets were downloaded from the MSigDB database, yielding 520 iron metabolism-related genes. The final nine hub genes associated with iron metabolism and AD were obtained by differential analysis and WGCNA in brain tissue samples from GSE132903. GO analysis revealed that these genes were mainly involved in two major biological processes, autophagy and iron metabolism. Through stepwise regression and logistic regression analyses, we selected four of these genes to construct a diagnostic model of AD. The model was validated in blood samples from GSE63061 and GSE85426, and the AUC values showed that the model had a relatively good diagnostic performance. In addition, the immune cell infiltration of the samples and the correlation of different immune factors with these hub genes were further explored. The results suggested that these genes may also play an important role in immunity to AD. Finally, eight drugs targeting these nine hub genes were retrieved from the DrugBank database, some of which were shown to be useful for the treatment of AD or other concomitant conditions, such as insomnia and agitation. In conclusion, this model is expected to guide the diagnosis of patients with AD by detecting the expression of several genes in the blood. These hub genes may also assist in understanding the development and drug treatment of AD.
... It has been previously shown how the direct and indirect (through ROS increase) interaction of Aβ with mitochondria disrupts the function of different components of the electron transport chain, thus affecting cellular respiration [47,48]. Here, we report that Aβ25-35 induces an alteration of the whole mitochondrial respiratory chain, decreasing basal respiration, ATP production, and maximal respiration. ...
Vascular brain pathology constitutes a common feature in neurodegenerative diseases that could underlie their development. Indeed, vascular dysfunction acts synergistically with neurodegenerative changes to exacerbate the cognitive impairment found in Alzheimer’s disease. Different injuries such as hypertension, high glucose, atherosclerosis associated with oxidized low-density lipoprotein or inflammation induce NADPH oxidase activation, overproduction of reactive oxygen species, and apoptosis in endothelial cells. Since it has been shown that pretreatment of cultured endothelial cells with the lipophilic antioxidant coenzyme Q10 (CoQ10) displays a protective effect against the deleterious injuries caused by different agents, this study explores the cytoprotective role of different CoQs homologues against Aβ25–35-induced damage and demonstrates that only pretreatment with CoQ10 protects endothelial brain cells from Aβ25–35-induced damage. Herein, we show that CoQ10 constitutes the most effective ubiquinone in preventing NADPH oxidase activity and reducing both reactive oxygen species generation and the increase in free cytosolic Ca2+ induced by Aβ25–35, ultimately preventing apoptosis and necrosis. The specific cytoprotective effect of CoQ with a side chain of 10 isoprenoid units could be explained by the fact that CoQ10 is the only ubiquinone that significantly reduces the entry of Aβ25–35 into the mitochondria.
... Therefore, the cerebral metabolic rate of oxygen utilization (CMRO 2 ) is a key metric to elucidate brain complex bioenergetic processes in normal conditions and in the context of neurodegenerative pathologies such as Alzheimer's disease (AD). In AD, accumulation of amyloid beta in the brain has been associated with a defect in mitochondrial function [1] and reduced CMRO 2 have long been reported in patients [2]. However, whether the defect in oxidative metabolism is the cause the pathological manifestation or rather results from disease progression is still unclear. ...
The cerebral metabolic rate of oxygen consumption (CMRO2) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO2 can be measured by direct 17O magnetic resonance imaging (17O-MRI) of H217O signal changes during inhalation of 17O-labeled oxygen gas. In this study, we built a simple gas distribution system and used 3D zero echo time (ZTE-)MRI at 11.7 T to measure CMRO2 in the APPswe/PS1dE9 mouse model of amyloidosis. We found that CMRO2 was significantly lower in the APPswe/PS1dE9 brain than in wild-type at 12–14 months. We also estimated cerebral blood flow (CBF) from the post-inhalation washout curve and found no difference between groups. These results suggest that the lower CMRO2 observed in APPswe/PS1dE9 is likely due to metabolism impairment rather than to reduced blood flow. Analysis of the 17O-MRI data using different quantification models (linear and 3-phase model) showed that the choice of the model does not affect group comparison results. However, the simplified linear model significantly underestimated the absolute CMRO2 values compared to a 3-phase model. This may become of importance when combining several metabolic fluxes measurements to study neuro-metabolic coupling.
... The major Aβ binding partners associated with AD are cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10). These interactions have been shown to lead to mitochondrial dysfunctions [3,19], including impaired energy metabolism [20], production of reactive oxygen species (ROS) [21], perturbation in calcium homeostasis [22], and formation and opening of the mitochondrial permeability transition pores (mPTPs) [23]. However, the exact mechanisms behind these processes remain largely unknown. ...
Progressive mitochondrial dysfunction due to the accumulation of amyloid beta (Aβ) peptide within the mitochondrial matrix represents one of the key characteristics of Alzheimer’s disease (AD) and appears already in its early stages. Inside the mitochondria, Aβ interacts with a number of biomolecules, including cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), and affects their physiological functions. However, despite intensive ongoing research, the exact mechanisms through which Aβ impairs mitochondrial functions remain to be explained. In this work, we studied the interactions of Aβ with cypD and 17β-HSD10 in vitro using the surface plasmon resonance (SPR) method and determined the kinetic parameters (association and dissociation rates) of these interactions. This is the first work which determines all these parameters under the same conditions, thus, enabling direct comparison of relative affinities of Aβ to its mitochondrial binding partners. Moreover, we used the determined characteristics of the individual interactions to simulate the concurrent interactions of Aβ with cypD and 17β-HSD10 in different model situations associated with the progression of AD. This study not only advances the understanding of Aβ-induced processes in mitochondria during AD, but it also provides a new perspective on research into complex multi-interaction biomolecular processes in general.
... • Abnormalities in mitochondrial complexes reduce mitochondrial enzyme activity that is vital in neuronal degeneration and death [47,[49][50][51][52]. ...
... Pro-apoptosis genes p53, NOS and NOX, which will result in reduced expression of genes encoding mitochondria-encoded complexes IV and V, function in the frontal lobe [38]. Undoubtedly, abnormalities in mitochondrial complexes, especially the activity of complex IV, which is the most documented reduction of mitochondrial enzyme activity that plays a vital role in cell degeneration and death, is seen in cognitive dysfunctions [49][50][51][52]. A study by Correia et al. [101] showed that rats administered with streptozotocin (STZ)-through intracerebroventricular (icv) injection experienced brain insulin resistance in addition to mitochondrial abnormalities with increased free radical levels. ...
Gestational diabetes mellitus (GDM) carries many risks, where high blood pressure, preeclampsia and future type II diabetes are widely acknowledged, but less focus has been placed on its effect on cognitive function. Although the multifactorial pathogenesis of maternal cognitive impairment is not completely understood, it shares several features with type 2 diabetes mellitus (T2DM). In this review, we discuss some key pathophysiologies of GDM that may lead to cognitive impairment, specifically hyperglycemia, insulin resistance, oxidative stress, and neuroinflammation. We explain how these incidents: (i) impair the insulin-signaling pathway and/or (ii) lead to cognitive impairment through hyperphosphorylation of τ protein, overexpression of amyloid-β and/or activation of microglia. The aforementioned pathologies impair the insulin-signaling pathway primarily through serine phosphorylation of insulin receptor substances (IRS). This then leads to the inactivation of the phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) signaling cascade, which is responsible for maintaining brain homeostasis and normal cognitive functioning. PI3K/AKT is crucial in maintaining normal cognitive function through the inactivation of glycogen synthase kinase 3β (GSκ3β), which hyperphosphorylates τ protein and releases pro-inflammatory cytokines that are neurotoxic. Several biomarkers were also highlighted as potential biomarkers of GDM-related cognitive impairment such as AGEs, serine-phosphorylated IRS-1 and inflammatory markers such as tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), leptin, interleukin 1β (IL-1β), and IL-6. Although GDM is a transient disease, its complications may be long-term, and hence increased mechanistic knowledge of the molecular changes contributing to cognitive impairment may provide important clues for interventional strategies.
... Mitochondrial structural changes promote respiratory chain dysfunction which leads to overproduction of ROS and decreases ATP level. Finally, it will lead to energy deficiency, neuronal death and NDs (Starkov and Beal, 2008;Readnower et al., 2011). Aβ toxicity induces mitochondrial dysfunction by altering the mitochondrial dynamics (fission and fusion) process. ...
Neurodegenerative diseases (NDs) are the group of disorder that includes brain, peripheral nerves, spinal cord and results in sensory and motor neuron dysfunction. Several studies have shown that mitochondrial dynamics and their axonal transport play a central role in most common NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) etc. In normal physiological condition, there is a balance between mitochondrial fission and fusion process while any alteration to these processes cause defect in ATP (Adenosine Triphosphate) biogenesis that lead to the onset of several NDs. Also, mitochondria mediated ROS may induce lipid and protein peroxidation, energy deficiency environment in the neurons and results in cell death and defective neurotransmission. Though, mitochondria is a well-studied cell organelle regulating the cellular energy demands but still, its detail role or association in NDs is under observation. In this review, we have summarized an updated mitochondria and their possible role in different NDs with the therapeutic strategy to improve the mitochondrial functions.
... The association between Aβ toxicity, mitochondrial dysfunction, oxidative stress and neuronal death has been well studied. Aβ increases production of mitochondrial ROS [31] and mitochondrial Ca ++ mobilization may contribute to this process [32]. Because mitochondrial DNA is inherited maternally, brain hypometabolism is more pronounced in AD patients who have a maternal family history of AD than those with a paternal family history or those with a negative family history [33]. ...
Alzheimer's disease (AD) is manifested by regional cerebral hypometabolism. Sirtuin 3 (Sirt3) is localized in mitochondria and regulates cellular metabolism, but the role of Sirt3 in AD-related hypometabolism remains elusive. We used expression profiling and weighted gene co-expression network analysis (WGCNA) to analyze cortical neurons from a transgenic mouse model of AD (APPSwInd). Based on WGCNA results, we measured NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and its deacetylation activity, and ATP production across both in vivo and in vitro models. To investigate the effect of Sirt3 on amyloid-β (Aβ)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aβ-related hypometabolism. In APP mice, the NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and activity, and ATP production were all reduced compared to the control. As a result, learning and memory performance were impaired in 9-month-old APP mice compared to wild type controls. Using hippocampal HT22 cells model, Sirt3 overexpression increased Sirt3 deacetylation activity, rescued mitochondria function, and salvaged ATP production, which were damaged by Aβ. Sirt3 plays an important role in regulating Aβ-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy.
... In AD, there are a well-documented deficit in both complex I and IV [4,85,86]. These deficits are thought to be due to the neuronal toxicity induced by amyloid β peptide (Aβ), an important component of AD pathogenesis, in that Aβ accumulates in mitochondria, directly inhibits mitochondrial enzymes, perpetuates oxidative stress, and leads to a hypometabolic state, which causes mitochondrial dysfunction [87][88][89][90]. The meta-analysis supported these findings in terms of downregulated complex I and IV in the blood [57,[91][92][93][94][95][96][97][98], frontal cortex [38,44,56,[99][100][101][102][103][104], motor cortex [102,105,106], occipital cortex [44,107,108], parietal cortex [36,44,52,102,107,108], temporal/entorhinal cortex [37,44,52,54,99,102,[107][108][109][110] and hippocampus [33,34,36,44,52,99,102,106,[111][112][113][114]. ...
Complex I (NADH dehydrogenase, NDU) and complex IV (cytochrome-c-oxidase, COX) of the mitochondrial electron transport chain have been implicated in the pathophysiology of major psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), as well as in neurodegenerative disorders, such as Alzheimer disease (AD) and Parkinson disease (PD). We conducted meta-analyses comparing complex I and IV in each disorder MDD, BD, SZ, AD, and PD, as well as in normal aging. The electronic databases Pubmed, EMBASE, CENTRAL, and Google Scholar, were searched for studies published between 1980 and 2018. Of 2049 screened studies, 125 articles were eligible for the meta-analyses. Complex I and IV were assessed in peripheral blood, muscle biopsy, or postmortem brain at the level of enzyme activity or subunits. Separate meta-analyses of mood disorder studies, MDD and BD, revealed moderate effect sizes for similar abnormality patterns in the expression of complex I with SZ in frontal cortex, cerebellum and striatum, whereas evidence for complex IV alterations was low. By contrast, the neurodegenerative disorders, AD and PD, showed strong effect sizes for shared deficits in complex I and IV, such as in peripheral blood, frontal cortex, cerebellum, and substantia nigra. Beyond the diseased state, there was an age-related robust decline in both complexes I and IV. In summary, the strongest support for a role for complex I and/or IV deficits, is in the pathophysiology of PD and AD, and evidence is less robust for MDD, BD, or SZ.
