Table 2 - uploaded by Andrea Kwakowsky
Content may be subject to copyright.
Source publication
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the vertebrate brain. In the past, there has been a major research drive focused on the dysfunction of the glutamatergic and cholinergic neurotransmitter systems in Alzheimer's disease (AD). However, there is now growing evidence in support of a GABAergic contribution to t...
Citations
... GABAergic dysfunction is a key factor: postmortem and in-vivo studies indicate reduced cortical GABA levels and interneuron loss in AD. 141 In previous work, 111 we used the LaNMM to represent the gradual dysfunction of PV interneurons due to Amyloid Beta oligomer toxicity and the subsequent loss of excitatory pyramidal neurons associated with advancing tau pathology. These mechanisms allowed our model to reproduce the full spectrum of AD electrophysiological biomarkers across disease development: early hyper-excitability-manifested as increased alpha synchrony and transient gamma enhancement-in preclinical and mild cognitive impairment stages, and later hypo-activationcharacterized by a dominance of slow-wave (delta/theta) activity and diminished alpha/gamma power-in moderate-to-severe AD. ...
Predictive coding frameworks suggest that neural computations rely on hierarchical error minimization, where sensory signals are evaluated against internal model predictions. However, the neural implementation of this inference process remains unclear.
We propose that cross-frequency coupling (CFC) furnishes a fundamental mechanism for this form of inference. We first demonstrate that our previously described laminar neural mass model (LaNMM) supports two key forms of CFC: (i) Signal-Envelope Coupling (SEC), where low-frequency rhythms modulate the amplitude envelope of higher-frequency oscillations, and (ii) Envelope-Envelope Coupling (EEC), where the envelopes of slower oscillations modulate the envelopes of higher-frequency rhythms. Then, we propose that - by encoding information in signals and their envelopes - these processes instantiate a hierarchical ``Comparator'' mechanism at the columnar level. Specifically, SEC generates fast prediction-error signals by subtracting top-down predictions from bottom-up oscillatory envelopes, while EEC operates at slower timescales to instantiate gating - a critical computational mechanism for precision-weighting and selective information routing.
To establish the face validity - and clinical implications of - this proposal, we model perturbations of these CFC mechanisms to investigate their roles in pathophysiological and altered neuronal function. We illustrate how, in disorders such as Alzheimer's disease, disruptions in gamma oscillations following dysfunction in fast-spiking inhibitory interneurons impact Comparator function with an aberrant amplification of prediction errors in the early stages and a drastic attenuation in late phases of the disease. In contrast, by increasing excitatory gain, serotonergic psychedelics diminish the modulatory effect of predictions, resulting in a failure to attenuate prediction error signals (c.f., a failure of sensory attenuation). Together, these results establish cross-frequency coupling - across temporal scales - as candidate computational processes underlying hierarchical predictive coding in health and disease.
... Numerous studies have documented reduced levels of GABA in both the cerebrospinal fluid (CSF) and temporal cortex of individuals with AD 33,34 and expression of GABA transporter also changes in human AD hippocampus, subiculum, entorhinal cortex and superior temporal gyrus. 35 It has been revealed that the subunit composition of GABA A Rs is altered in certain regions of the cortex and hippocampus in AD, 36 while in a mouse model of AD, reduction in the neuronal surface of post and presynaptic GABA A Rs receptors in the hippocampus 37,38 and complete restoration of impaired spike probability, synaptic plasticity, and learning and memory in a mouse model of AD can be achieved by inhibiting the production or release of GABA from reactive astrocytes. 39 In patients with DM, studies show an elevation in GABA levels within the medial prefrontal cortex, and these elevated GABA levels are inversely associated with memory function. ...
Background
The connection between diabetes-associated cognitive dysfunction (DACD) and Alzheimer’s disease (AD) has been shown in several observational studies. However, it remains controversial as to how the two related.
Objective
To explore shared genes and pathways between DACD and AD using bioinformatics analysis combined with biological experiment.
Methods
We analyzed GEO microarray data to identify DEGs in AD and type 2 diabetes mellitus (T2DM) induced-DACD datasets. Weighted gene co-expression network analysis was used to find modules, while R packages identified overlapping genes. A robust protein-protein interaction network was constructed, and hub genes were identified with Gene ontology enrichment and Kyoto Encyclopedia of Genome and Genome pathway analyses. HT22 cells were cultured under high glucose and amyloid-β 25–35 (Aβ25-35) conditions to establish DACD and AD models. Quantitative polymerase chain reaction with reverse transcription verification analysis was then performed on intersection genes.
Results
Three modules each in AD and T2DM induced-DACD were identified as the most relevant and 10 hub genes were screened, with analysis revealing enrichment in pathways such as synaptic vesicle cycle and GABAergic synapse. Through biological experimentation verification, 6 key genes were identified.
Conclusions
This study is the first to use bioinformatics tools to uncover the genetic link between AD and DACD. GAD1, UCHL1, GAP43, CARNS1, TAGLN3, and SH3GL2 were identified as key genes connecting AD and DACD. These findings offer new insights into the diseases’ pathogenesis and potential diagnostic and therapeutic targets.
... It plays an important role in maintaining the balance of excitability and inhibition in the brain. 47 Literature evidence suggests that GABAergic remodeling is involved in the pathogenesis of AD. 39,47 Up to 22% of people with AD experience seizures. GABAergic dysfunction has long been considered to be associated with the development of epilepsy and persistent epileptic states. ...
... It plays an important role in maintaining the balance of excitability and inhibition in the brain. 47 Literature evidence suggests that GABAergic remodeling is involved in the pathogenesis of AD. 39,47 Up to 22% of people with AD experience seizures. GABAergic dysfunction has long been considered to be associated with the development of epilepsy and persistent epileptic states. ...
The rising incidence of Alzheimer's disease (AD) and the associated economic impacts has prompted a global focus in the field. In recent years, there has been a growing understanding of the pathogenic mechanisms of AD, including the aggregation of β‐amyloid, hyperphosphorylated tau, and neuroinflammation. These processes collectively lead to neurodegeneration and cognitive decline, which ultimately results in the loss of autonomy in patients. Currently, there are three main types of AD treatments: clinical tools, pharmacological treatment, and material interventions. This review provides a comprehensive analysis of the underlying etiology and pathogenesis of AD, as well as an overview of the current prevalence of AD treatments. We believe this article can help deepen our understanding of the AD mechanism, and facilitate the clinical translation of scientific research or therapies, to address this global problem of AD.
... It then binds to GABA receptors on postsynaptic neurons, leading to neuronal activity inhibition. 36 GABA recep-tors are classified into the ionotropic GABA A receptors and metabotropic GABA B receptors. 37 There are 19 GABA A receptor subunits (including a1-6, b1-3, g1-3, d, ε, q, p, and r1-3) and two principal GABA B receptor subunits (GABA B1 and GABA B2 ). ...
... First, given that grow-ing evidence demonstrated that aberrant glutamatergic system activation and GABAergic dysfunction resulted in neuronal hyperexcitability and degeneration in the AD brain(Bi et al., 2020), the enlarged GABAergic neurons could be a compensatory mechanism against hyperexcitability. Second, GABAergic neurons appear to be relatively spared during the pathogenesis of AD(Govindpani et al., 2017), which may enhance their survival prospects under AD conditions. ...
Emerged evidence indicated that stimulating hippocampal neurogenesis is a potential strategy for restoring cognition in AD. Mitogen‐activated protein kinases (MAPKs) play an essential role in neurogenesis. Meanwhile, the enzymatic power of the phosphatases is much greater than that of kinases. Dual‐specificity phosphatase 16 (DUSP16), known to as a phosphatase negatively regulate MAPKs, may be implicated in neural differentiation. Nevertheless, the effect of DUSP16 on cognitive disorders by stimulating neural progenitor cell (NPC) differentiation in AD mice remains unclear. Our study demonstrates an association between DUSP16 SNPs and clinical progression in individuals with mild cognitive impairment (MCI). Besides, increased DUSP16 expression was detected in both 3xTg and SAMP8 mouse models of AD, accompanied by NPC neural differentiation impairments. By silencing DUSP16, the induction of neural differentiation, synaptic transmission, and cognitive benefits were observed in both AD mice. Furthermore, DUSP16 was involved in the process of NPC differentiation through regulating c‐Jun N‐terminal kinase (JNK) phosphorylation and SOX2 expression. Moreover, ETS transcription factor (ELK1) was involved in the DUSP16 transcription, which resulted in the upregulation of DUSP16 at the state of AD. Our data uncovers a potential regulatory role for DUSP16 in adult hippocampal neurogenesis (AHN) and provides a possibility to find a novel strategy for AD intervention.
... More recently, the imbalance in the glutamate/γ amino butyric acid (GABA) ratio has been addressed to justify this greater excitability. 12 Although not a consensus, reductions in hippocampal GABA levels have been found in both patients, and in animal models of AD. 13,14 However, attempts to employ cerebrospinal fluid (CSF) levels of these neurotransmitters as markers of disease have failed. 15 Another indication of neurotransmission alteration in AD is the increase in monoamine oxidase B (MAO-B), a principally astroglial enzyme that is responsible for metabolizing catecholamines. ...
... The imbalance in the glutamate/GABA ratio has been addressed to justify the greater excitability observed in AD, as supported by reduced levels of GABA in brain tissue, in AD patients and in animal models. [13][14][15] However, this is inconsistent with the potentially greater production of GABA, via MAO-B. To address this discrepancy, we investigated the sources and destinations of GABA, in the STZ-induced AD model, in the pre-amyloid and amyloid phases. ...
Background
In the sporadic model of Alzheimer's disease (AD), induced by intracerebroventricular streptozotocin (STZ) administration, cognitive impairment is accompanied by specific astrocytic changes in the hippocampus prior to amyloid deposition.
Objective
Hypothesizing that the synthesis of GABA, via MAO-B, contributes to ammonia elevation, thereby compromising antioxidant defense and ATP synthesis, and possibly contributing to cognitive damage, we determined the hippocampal levels of glutamine synthetase (GS), monoamine oxidase B (MAO-B) and other enzymes related to GABA metabolism.
Methods
Immunoblotting and RT-PCR assays were carried out in hippocampal samples of Wistar rats, at 4 and 16 weeks post-STZ, in the sporadic STZ-induced AD model, corresponding to the pre-amyloid and amyloid phases, respectively.
Results
We observed a reduction in GS activity and increased MAO-B content, both in 4 weeks and in 16 weeks, reinforcing the idea that astroglial dysfunction precedes the amyloid phase. These alterations were accompanied by an increase in the content of ornithine decarboxylase 1 (ODC1), which catalyzes the synthesis of putrescine (substrate for GABA synthesis, via MAO-B), and a reduction in the gene expression of arginine-glycine amidinotransferase (AGAT), an enzyme involved in the synthesis of creatine, and in the generation of GABA agonists. These changes were only seen in the amyloid phase of the AD model.
Conclusions
Our findings contribute to explain the greater damage that occurs in energy metabolism at this stage, in addition to the greater GABAergic loss. The changes reinforce the importance of the STZ model and further our understanding of the changes in both AD phases.
... At GABAergic synapses, fast inhibitory postsynaptic currents are mediated by GABA A Rs. While there is still debate about how the expression of these receptors changes in AD, the majority of studies point to either a decrease or no change in functional receptor expression along with changes in subunit composition in the hippocampus and cortex (Limon et al. 2012;Govindpani et al. 2017;Kwakowsky et al. 2018;Carello-Collar et al. 2023). However, less is known about how GABA A Rs are affected in the MS/DBB, and it is possible that upregulation of GABA A R signaling precedes a loss of receptors. ...
Hippocamposeptal (HS) neurons send GABAergic projections from the hippocampus to the medial septum/diagonal band of Broca (MS/DBB) as part of a reciprocal loop that is critical for memory. HS neurons are proposed to be particularly sensitive to the deleterious effects of pathological exposure to amyloid-β (Aβ), as would occur during Alzheimer’s disease (AD). However, it is not known how HS GABA release in the MS/DBB is altered during the progression of AD. To target HS neurons in a mouse model of AD, we crossed SST-Cre mice to 5XFAD mice and performed stereotaxic injections of Cre-dependent AAV containing mCherry/channelrhodopsin-2 (ChR2) into the hippocampus of offspring at 4, 6, 9, and 12 months. We used optogenetics to selectively stimulate HS terminals while performing whole-cell patch-clamp recordings from MS/DBB neurons in slices. There was a transient reduction in HS-inhibitory postsynaptic current (IPSC) amplitude in female 5XFAD mice at 6 months, but no difference in males at any age, and no difference in paired-pulse ratio in either sex at any age. When bath applying the GABABR agonist, baclofen, we found a larger decrease in HS-IPSC amplitude in 5XFAD females at 9 months and 5XFAD males at 12 months. In 12-month-old 5XFAD females, response to baclofen was significantly reduced. These data suggest that there is a transient increase in responsiveness to GABABR activation in 5XFAD mice that occurs earlier in females than in males. These sex-specific changes to HS function are likely to impact the relay of information between the hippocampus and MS/DBB.
... For example, Dilmore et al. (2023) exploring dietary intervention effects on the microbiome in adults at risk for AD showed that the low-fat American Heart Association Diet increased GABA production in MCI individuals by increasing GABA-producing Alistipes. This finding contradicted previous studies reporting dysfunction of GABA signaling aggravating AD pathology and showing lower levels of GABA in postmortem brain tissue from AD patients (Govindpani et al., 2017;Andersen et al., 2022). A previous meta-analysis study has found that an overgrowth of Bacteroides in US-based AD cohorts, while this pattern was not observed in Chinese cohorts. ...
Background
The gut microbiota (GM) is hypothesized to play roles in Alzheimer’s disease (AD) pathogenesis. In recent years, many GM composition and abundance investigations in AD patients have been conducted; however, despite this work, some results remain controversial. Therefore, we conducted a systematic review and meta-analysis using 16S ribosomal RNA (16S rRNA) sequencing to explore GM alterations between patients with AD spectrum and healthy controls (HCs).
Methods
A systematic and comprehensive literature search of PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc database, WanFang database and Social Sciences Citation Index databases was conducted from inception to January 2023. Inclusion and exclusion criteria were strictly defined, and two researchers independently screened and extracted information from selected studies. Data quality were evaluated according to the “Cochrane system evaluator manual” and pooled data were comprehensively analyzed using Stata 14 software with standardized mean differences (SMDs) and 95% confidence intervals (95% CIs) used to measure effect sizes. Also, geographical heterogeneity effects (related to cohorts) on GM abundance were examined based on subgroup meta-analyses if sufficient studies reported outcomes. Finally, publication bias was assessed using funnel plots.
Results
Out of 1566 articles, 13 studies involving 581 patients with AD spectrum and 445 HCs were deemed eligible and included in our analysis. In summary, a decreased microbiota alpha diversity and a significantly distinct pattern of clustering with regard to beta diversity were observed in AD spectrum patients when compared with HCs. Comparative analyses revealed a decreased Ruminococcus, Faecalibacterium, Lachnospira, Dialister, Lachnoclostridium, and Roseburia abundance in AD spectrum patients while Phascolarctobacterium, Lactobacillus, and Akkermansia muciniphila were more enriched in patients when compared to HCs. Furthermore, regional variations may have been in play for intestinal microbes such as Bacteroides, Bifidobacterium, and Alistipes.
Conclusion
Our meta-analysis identified alterations in GM abundance in patients with AD spectrum, with 12 genera from four major phyla significantly associated with AD. Moreover, we provided evidence for region-specific alterations in Bacteroides, Bifidobacterium, and Alistipes abundance. These findings may have profound implications for the development of innovative GM-based strategies to prevent and treat AD.
Systematic review registration
https://doi.org/10.37766/inplasy2024.6.0067, identifier INPLASY202460067.
... Слід зазначити, що ГАМК, основний інгібуючий нейромедіатор у ЦНС людини, бере участь у формуванні неврологічних процесів і пізнавальної здатності, а пов'язані з ГАМК функції, на думку фахівців, можуть бути важливим чинником у механізмах патогенезу хвороби Альцгеймера [5,24,25]. ...
Огляд присвячено зв’язку мікробіома людини з розвитком нейродегенеративної патології. Сьогодні мікробіом розглядають як додатковий орган людини, який бере активну участь у травленні, метаболічних процесах, підтриманні цілісності епітеліального бар’єра, зміцненні імунної системи тощо. Останніми роками отримано значну кількість переконливих доказів величезного потенціалу дії мікробіома на різні процеси в організмі людини, зокрема його впливу на поведінку та біохімію мозку. Тонкі механізми розвитку й патогенезу різних форм нейродегенеративної патології поки що повністю не розшифровано, проте результати численних досліджень підтверджують участь кишкового мікробіома в підтриманні здоров'я мозку, а також вказують на тригерну роль порушеної осі «кишечник — мікробіом — мозок» у розвитку нейродегенеративної патології. На думку фахівців, профілактика порушення і відновлення мікробіома з використанням окремих видів пробіотиків та інших засобів мікробіомної терапії може стати одним з інструментів профілактики нейродегенеративних захворювань і важливим компонентом комплексних схем лікування хворих.
... Prior research has already demonstrated decreased GABAergic neurotransmission in both the hippocampus and cerebral cortex of adult Wistar rats fed with HFD [46]. Additionally, inhibitory activity triggered by GABAergic signaling undergoes alterations during aging, which can lead to hippocampal hyperactivity, memory impairments [47,48], cognitive decline, and neurological symptoms associated with Alzheimer's disease [49]. In contrast, CR was found to elevate GABA levels in both obese and nonobese animals. ...
Obesity and aging collectively potentiate inflammatory responses, particularly within the central nervous system. Managing obesity presents a significant challenge, even more so considering the context of aging. Caloric restriction (CR) has been extensively documented in the literature for its multiple health benefits. Motivated by these findings, we hypothesized that CR could serve as a valuable intervention to address the brain alterations and cognitive decline associated with obesity in aged rats. Our investigation revealed that cafeteria diet increased hippocampal and hypothalamic transcripts related to neuroinflammation, along with cognitive deficits determined in the object recognition test in 18-month-old male rats. Western blot data indicate that the obesogenic diet may disrupt the blood–brain barrier and lead to an increase in Toll-like receptor 4 in the hippocampus, events that could contribute to the cognitive deficits observed. Implementing CR after the onset of obesity mitigated neuroinflammatory changes and cognitive impairments. We found that CR increases GABA levels in the hippocampus of aged animals, as demonstrated by liquid chromatography coupled with mass spectrometry analysis. These findings underscore the potential of CR as a therapeutic opportunity to ameliorate the neuroinflammatory and cognitive alterations of obesity, especially in the context of aging.
Graphical Abstract
Cafeteria diet induced disruptions in the blood–brain barrier, neuroinflammation, and cognitive deficits in aged animals, ameliorated by subsequent 30% calorie restriction (CR) for 5 weeks.
