Alzheimer's Disease Cognitive Impairment Research Articles

Downregulation of ATF-4 Attenuates the Endoplasmic Reticulum Stress-Mediated Neuroinflammation and Cognitive Impairment in Experimentally Induced Alzheimer's Disease Model.

Protein aggregation is invariably associated with the inflammation as a factor in Alzheimer's disease (AD). We investigated the interaction between downstream factors of endoplasmic reticulum (ER) stress pathway and inflammation, with implications in cognitive impairment in AD. Amyloid-β(Aβ)(1-42) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats to experimentally develop AD. The cognitive impairment was assessed by measuring behavioral parameters such as Morris water maze and novel object recognition tests. Levels of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α and anti-inflammatory cytokines IL-4 and IL-10 were measured by the enzyme-linked immunosorbent assay (ELISA) in different rat brain regions. Inflammatory marker proteins such as cyclo-oxygenase (COX)-2 and phosphorylation of nuclear factor kappa B(NF-КB) (p65) were measured by the western blotting. Gene expression of ER stress downstream factors such as ATF-4, CHOP, and GADD-34 was analyzed by qRT-PCR. Histological studies were performed to check Aβ accumulation and neuronal degeneration. Integrated stress response inhibitor (ISRIB) was used to confirm the specific role of ER stress-mediated inflammation in cognitive impairment. Administration of Aβ(1-42) resulted in alteration in levels of inflammatory cytokines, inflammatory proteins, and mRNA levels of ER stress downstream factors. ISRIB treatment resulted in attenuation of Aβ(1-42)-induced ER stress, inflammation, neurodegeneration, and cognitive impairment in rats. These results indicate that ER stress-mediated inflammation potentiates the cognitive impairment in AD. An understanding of cascade of events, interaction of ER stress which was a hallmark of the present investigation together with inflammation and modulation of downstream signalling factors could serve as potent biomarkers to study AD progression.

Choline alfoscerate in the correction of cognitive impairment

In preclinical and clinical studies, choline alfoscerate (CA) has proven to be highly effective in the correction of cognitive impairment (CI). The clinical effect of CA is seen in the improvement of mental activity, concentration, ability to remember and recall information, cognitive and behavioural responses, elimination of emotional instability and apathy. Experimental studies have shown the effectiveness of CA in preventing atrophic changes in the cerebral cortex. Based on several studies conducted on the use of CA in the treatment of CI, it can be concluded that oral administration of CA at a dose of 600 mg/day can be recommended both as monotherapy and as part of complex therapy in patients with cerebrovascular diseases such as chronic cerebral ischemia. As part of complex therapy for CI in Alzheimer's disease, a combination of CA at a dose of 1200 mg/day with donepezil at a dose of 10 mg/day may be recommended. Several studies have demonstrated the efficacy of CA in the treatment of post-COVID and post-traumatic CI. The efficacy of CA administration in the treatment of CI (including vascular dementia) following ischemic stroke and transient ischemic attacks has been demonstrated. When CA is taken, there is also a reduction in anxiety and depressive disorders, asthenia, the severity of pain symptoms and changes in coordination. The duration of therapy should be 60 to 90 days, depending on the severity of CI, followed by an observation phase of up to 2 years. For successful treatment with CA, it is necessary to carry out repeated courses of CI treatment. Today, a new drug Cerpechol (600 mg/7 ml) has appeared on the Russian market, which has all the effects of CA. The convenience of the new form (oral solution) makes it possible to use it in patients with swallowing disorders.

Isolinderalactone Ameliorates the Pathology of Alzheimer's Disease by Inhibiting the JNK Signaling Pathway.

Neuronal cell damage is a major cause of cognitive impairment in Alzheimer's disease (AD). Multiple factors, such as amyloid deposition, tau hyperphosphorylation, and neuroinflammation, can lead to neuronal cell damage. Therefore, the development of multi-target drugs with broad neuroprotective effects may be an effective strategy for the treatment of AD. Natural products have become an important source of drug discovery because of their good pharmacological activity, multiple targets, and low toxicity. In this study, we screened a natural compound library and found that the fat-soluble sesquiterpene natural compound isolinderalactone (Iso) extracted from the dried root pieces of Lindera aggregata had the ability to alleviate cellular damage induced by β-amyloid-1-42 (Aβ1-42). The role and mechanism of Iso in AD have not yet been reported. Herein, we demonstrated that Iso significantly reduced the level of apoptosis in PC12 cells. Besides, Iso treatment reduced amyloid deposition, neuron apoptosis, and neuroinflammation, ultimately improving the cognitive dysfunction of APP/PS1 (APPswe/PSEN 1dE9) mice. Notably, Iso-10 mg/kg showed superior improved effects in APP/PS1 mice compared with the positive control drug donepezil-5 mg/kg. Mechanistically, the results of RNA sequencing combined with Western blots showed that Iso exerted its therapeutic effect by inhibiting the c-Jun N-terminal kinase (JNK) signaling pathway. Taken together, our findings suggest that Iso is a potential drug candidate for the treatment of AD.

Relação da atividade física com a melhora da qualidade de vida de pessoas com Doença de Alzheimer: revisão sistemática da literatura

The aim of this study is to report on the impact of physical activity in a palliative manner on the quality of life of people with Alzheimer's disease (AD). A literature review was conducted using scientific journal articles, theses, dissertations, and scientific websites that were evaluated for the present study. The bibliographic survey was carried out by consulting the following scientific databases: PubMed, Scielo, BVS Brasil. The search was retrospective, limiting itself to scientific papers published from February 2010 to February 2023. Physical activity can delay the expression of symptoms and cognitive impairment of AD, as well as increase protective mechanisms such as the release of neurotrophins and the hormone irisin. The combination of drug therapy with physical activity can also improve the quality of life of patients. Some studies indicate that light and moderate activities can contribute to the reduction of deficits in daily living activities and attenuate sleep disorders. Other studies show that physical activity can improve cognitive function, balance, and reduce the risk of falls in elderly people with AD. Walking seems to be a particularly beneficial physical activity for patients with AD. Although the studies presented in this review strongly indicate the benefits of physical activity for patients with AD, more research is needed to better elucidate the pathophysiology and treatment of the disease.

Astrocyte-specific knockout of YKL-40/Chi3l1 reduces Aβ burden and restores memory functions in 5xFAD mice

Glial cell-mediated neuroinflammation and neuronal attrition are highly correlated with cognitive impairment in Alzheimer’s disease. YKL-40 is a secreted astrocytic glycoprotein that serves as a diagnostic biomarker of Alzheimer’s disease. High levels of YKL-40 are associated with either advanced Alzheimer’s disease or the normal aging process. However, the functional role of YKL-40 in Alzheimer’s disease development has not been firmly established. In a 5xFAD mouse model of Alzheimer’s disease, we observed increased YKL-40 expression in the cerebrospinal fluid of 7-month-old mice and was correlated with activated astrocytes. In primary astrocytes, Aβ1-42 upregulated YKL-40 in a dose-dependent manner and was correlated with PI3-K signaling pathway activation. Furthermore, primary neurons treated with YKL-40 and/or Aβ1-42 resulted in significant synaptic degeneration, reduced dendritic complexity, and impaired electrical parameters. More importantly, astrocyte-specific knockout of YKL-40 over a period of 7 days in symptomatic 5xFAD mice could effectively reduce amyloid plaque deposition in multiple brain regions. This was also associated with attenuated glial activation, reduced neuronal attrition, and restored memory function. These biological phenotypes could be explained by enhanced uptake of Aβ1-42 peptides, increased rate of Aβ1-42 degradation and acidification of lysosomal compartment in YKL-40 knockout astrocytes. Our results provide new insights into the role of YKL-40 in Alzheimer’s disease pathogenesis and demonstrate the potential of targeting this soluble biomarker to alleviate cognitive defects in symptomatic Alzheimer’s disease patients.

Signatures of abnormal deviations in excitation‐inhibition balance for amyloid positive individuals

AbstractBackgroundDysfunctional excitation‐inhibition balance (EIB) is hypothesized to precede cognitive impairment in Alzheimer’s disease (AD); however, overlapping neuropathology (like amyloid plaques) can develop in cognitively normal (CN) and impaired (CI) individuals. We investigate EIB trajectories for individuals with significant amyloid (Aβ+).MethodMultimodal imaging was used to construct hybrid resting‐state structural connectomes (Fortel, Igor, et al. Network Neuroscience 6.2 (2022): 420‐444.), computing whole‐brain EIB based on 105 ROIs. This cohort (N = 185, 94 Female) aged 55‐90 (μ FEMALES = 74.9, and μ MALES 73) was limited to Aβ+ individuals with APOE genotyping (ε3/ε3, ε3/ε4, ε4/ε4); grouped further by clinical dementia rating (CDR), with CDR > 0 indicating CI. Imaging, Aβ+ classifications, CDR, and APOE were obtained from OASIS‐3: Longitudinal Multimodal Neuroimaging: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P30 AG066444, P50 AG00561, P30 NS09857781, P01 AG026276, P01 AG003991, R01 AG043434, UL1 TR000448, R01 EB009352. AV‐45 doses were provided by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly.ResultResults presented in Figure 1 suggest whole‐brain EIB in both CN sexes with Aβ+ decreases with increasing age (APOE‐ε4 agnostic). However, sex differences are highlighted with CI; regression analyses produce a marginally significant 4‐way interaction of age, sex, cognitive status, and APOE (P = 0.085, β = ‐0.013). Partial correlation of EIB with age, controlling for sex, APOE and cognitive status is also significant (P = 0.016, r = ‐0.18). Results indicate sex‐mediated EIB differences in individuals with CI, dominated by APOE‐ε4 in women rather than amyloid.ConclusionWe’ve demonstrated EIB deviations in cognitively impaired men and women that may be associated with AD neuropathology. Our findings are consistent with known AD sex differences and suggest novel multimodal connectomics may capture subtle disruptions in brain dynamics that traditional methods may not. Figure. 1. Whole‐brain excitation‐Inhibition balance (EIB) trajectories for amyloid positive (Aβ+) men and women. The cognitively normal (CN) group (rows A‐B) suggests no sex differences in EIB trajectories with age, while the cognitively impaired (CI) group (rows C‐D) begins to reveal distinct patterns of dysfunction (more significantly in women with APOE‐ε4). Note a value of 0.5 indicates perfect balance.

Evaluation of the association between circulatory markers of neuroinflammation and Alzheimer’s disease pathology

AbstractBackgroundIncreasing evidence suggests that neuroinflammation and astrogliosis have a prominent role in the spread of pathology and the development of cognitive impairment in Alzheimer’s disease (AD). Circulating plasma markers of neuroinflammation, such as the glial fibrillary acid protein (GFAP), have recently become available, and early observations suggest a robust association with brain pathology. Positron emission tomography (PET) is a molecular imaging technique that allows visualisation and quantification of AD pathology in vivo. The aim of this study was to evaluate the association between GFAP and AD pathology, and its interaction with cognitive decline.Method121 subjects from the Geneva Memory Centre underwent amyloid and tau PET, blood collection, and mini‐mental state examination (MMSE). Amyloid uptake was calculated as centiloid whereas tau was quantified as standardised uptake value ratio. Association of centiloid and tau with GFAP was assessed using a multivariate linear regression model, corrected for age, gender, and MMSE. Mediation analysis described the mediating effect of GFAP on the association between centiloid and tau. Ninety‐four subjects had a follow‐up MMSE after at least 12 months. Linear regression was used to assess the effect of GFAP on the annual rate of change of MMSE (corrected for centiloid, global tau, age, and gender). Mediation analysis was used to test whether the relationship between rate of MMSE change and tau could be explained by a mediation of GFAP.ResultThe mean (SD) age of the participants was 72.6 (7.6) years, and 61 of 121 subjects were men. GFAP was significantly associated with increased tau, but not with centiloid. GFAP partially mediated the effect of centiloid on global tau (mediated proportion = 14%, p = 0.03). The rate of MMSE change was significantly associated with GFAP, and global tau, but not with centiloid. Moreover, GFAP partially mediated the effect between global tau SUVR and change of MMSE scores (52%, p<0.01).ConclusionElevated GFAP is associated with tau. GFAP also partially explains the effect of amyloid pathology on tau accumulation and of tau pathology on subsequent cognitive decline. These results support neuroinflammation and astrogliosis as a relevant contributor to AD pathology, which can be monitored in blood.

Exploring Brain Functional Connectivity in Cognitively Healthy Individuals with Pathological CSF Amyloid/Tau

AbstractBackgroundDisrupted brain connectivity precedes cognitive impairment in Alzheimer’s disease (AD), affects self‐regulation and executive functions, and can be revealed by quantitative electroencephalography (qEEG). Neuroimaging research on AD progression has demonstrated structural and functional abnormalities in specific brain regions and connections. However, little is known about the changes in directional functional connectivity in pre‐symptomatic AD. We aim to explore the information flow in pre‐symptomatic AD during cognitive flexibility challenge.MethodDuring a task‐switching challenge, 21‐head channel EEG was recorded from 55 cognitively healthy individuals classified into two groups (9 were excluded from artifacts or suboptimal performance): with an abnormal (CH‐PAT, n = 27) versus normal (CH‐NAT or controls, n = 19) ratio of cerebrospinal fluid (CSF) amyloid/total‐tau. In the task‐switching paradigm, each trial included two stimuli, and participants were required to either name the ink color or read the word when color words were printed in different colors of ink. Only correctly responded trials were analyzed. Directed functional connectivity between brain regions was estimated with Partial Directed Coherence (PDC) in frontal, central, parietal, temporal, and occipital regions in alpha frequency band (8‐12 Hz) during word‐color trials. Two‐sided t‐tests were conducted, with p<0.05 considered the level for significance. No multiple comparison correction was used for this exploratory study.ResultPilot analysis shows significant differences between CH‐PATs and CH‐NATs: CH‐PATs has shown decreased information flow from the temporal and occipital regions compared to CH‐NATs with p‐values of 0.001 and 0.04, respectively. In addition, frontal brain regions have shown enhanced information flow in the CH‐PATs compared to CH‐NATs (p = 0.02) (Figs 1&2). Moreover, greater information flow between the medio‐frontal cortex and occipital regions was observed in CH‐PATS than CH‐NATS (Fig 1).ConclusionCompared to CH‐NATs, the enhanced connectivity in frontal regions in CH‐PATs suggests that their frontal brain regions are compensating for the damage caused by the amyloid/tau pathology. The decreased information flow from temporal and occipital regions in CH‐PATs may indicate a loss of relative functional importance of these regions. Our exploratory findings provide a novel and alternative approach for connectivity‐based analysis to identify the effects of amyloid/tau pathology in CH participants.

Global analysis of synapse‐enriched miRNA in Alzheimer’s disease temporal cortex post‐mortem

AbstractBackgroundSynapse loss is the major neuropathologic correlate of cognitive impairment in Alzheimer’s disease (AD). MicroRNA (miRNA) regulate synaptic plasticity and play a role in AD pathogenesis and therefore represent potential therapeutic targets. The aim of this study is to determine the role of miRNA‐mediated dysfunction at AD synapses.MethodWe prepared homogenates (H) and synaptosomes (SYN) from frozen post‐mortem temporal cortex tissue from 10 AD (mean age = 77.4±4.2) and 10 non‐pathological controls (CN; mean age = 72.3±5.9). We extracted (mirVana) and quantified miRNA using the TaqManR Advanced miRNA Assay, QuantstudioTM and OpenarrayTM system. Samples were normalized (median Ct). DeltaCt values calculated relative to control hsa‐miR‐16‐5p. We performed linear regression to identify differentially expressed (DE) miRNA across groups, controlling the false discovery rate (FDR) using the Benjamini‐Hochberg method. We considered DE miRNA with fold changes <0.8 or >1.2 (adj.p<0.05) in AD vs CN. We searched two predictive databases (TargetScan and miRDB) for gene targets of the DE miRNA and identified overrepresented target genes using the Panther database (PantherDB.org) after controlling the FDR.ResultOf the 751 miRNA included on the Openarray, we detected 411 in H and 432 in SYN, with 89% overlap between AD and CN in SYN. To enrich our analyses for miRNA that are predominantly present at the synapse, we took forward only the 47 miRNA with >1.2‐foldchange (adj.p<0.2) in SYN vs H in either AD or CN. miR‐132‐3p and miR‐132‐5p were under‐expressed (0.17‐fold, p = 0.001 and 0.35‐fold, p = 0.006, respectively) and miR‐181a‐3p was over‐expressed (2.13‐fold, p = 0.04) in AD compared to CN SYN. The 594 gene targets of upregulated synaptic miRNA (miR‐181a‐3p) were overrepresented in pathways regulating synaptic function and mitochondrial bioenergetics and integrity. The 474 and 1230 targets of downregulated synaptic miRNA (miR‐132‐3p and miR‐132‐5p, respectively) were overrepresented in the same pathways as well as pathways related to interleukin production, tau pathology, Abeta production, apoptotic signalling and oxidative stress.ConclusionThree synapse‐specific miRNA are differentially expressed at AD synapses and target genes involved in core AD‐related processes, thus making them promising therapeutic targets. Future studies will seek to validate these findings and determine the specificity for AD over other neurodegenerative diseases.

Bilingualism in the Clinical Diagnosis of Mild Cognitive Impairment and Dementia

AbstractBackgroundNeuropsychological assessments determine the presence of cognitive impairment in Alzheimer’s Disease and Related Dementias (ADRD). These tests are susceptible to the influence of cultural and linguistic variables. Bilingualism is a potential contributor to cognitive reserve in elderly individuals. Positive effects of bilingualism have been observed in executive function tasks, while negative effects have been reported on verbal fluency tests. Maintaining two active languages may modify cognitive and brain reserve among bilinguals, but evidence is inconsistent and contradictory. We investigated the relationship between bilingualism and neuropsychological test performance in aging participants from the 1Florida ADRC using a longitudinal design.MethodsWe studied 238 Latino older adults (age 71.79 ± 8.01 years old, 65% female). 158 Latino participants were Spanish‐English bilinguals; 80 were Spanish monolinguals. Bilingualism was assessed by a proficiency questionnaire. Six cognitive composites were developed (Figure 1). We investigated cognitive test change scores between language group, visit (2 visits: M = 14.61 months; SD = 3.52), and diagnosis (normal, MCI, dementia) using 2×2×3 repeated measures ANCOVAs (age and level of education). Cognitive scores were correlated with frontal and temporal brain volumes in bilinguals and monolinguals separately.ResultsMain effects of the diagnostic group and visit were significant for all composites (ps < .001), with the dementia group showing the lowest scores. No significant main effect of Bilingualism was observed for any of the composites. An interaction between visit and bilingualism was seen for the Trail Making Test B‐ A. Three‐way interactions were found between diagnostic groups, visit, and bilingualism for the Verbal composite and the Logical Memory delay subtest (part of the Memory composite). A more significant decline in the monolingual groups was observed, more so in the dementia group. Significant correlations were found between most composites in both language groups, being more related to the temporal than frontal lobe areas, using MRI volumetric measures.ConclusionBilingualism seems to interact with cognitive decline in aging. It is essential to consider the individual’s level of bilingualism to obtain an accurate assessment of cognitive impairment. The interaction of bilingualism with other sociodemographic and cognitive variables will be discussed.

RTMS regulates homotopic functional connectivity in the SCD and MCI patients

ObjectiveImpaired interhemispheric connectivity and corpus callosum atrophy have been linked to cognitive impairment in Alzheimer’s disease (AD). Existing evidence indicates that repetitive transcranial magnetic stimulation (rTMS) targeting the bilateral precuneus may enhance cognitive function in AD. This study aims to investigate the effects of precuneus rTMS on cognitive function, as well as alterations in interhemispheric functional connectivity (FC) and its structural basis in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI).MethodsA total of 14 patients with SCD and 16 patients with MCI were enrolled in this study and received 10 Hz rTMS intervention on the bilateral precuneus for 2 weeks. Neurocognitive scales, structural and functional magnetic resonance imaging were collected at enrollment and after the rTMS intervention. Interhemispheric FC was assessed using mirror homotopic functional connectivity (VMHC), while the structural equation modeling (SEM) was employed to analyze the relationship between corpus callosum volume, interhemispheric connectivity, and cognitive function after rTMS intervention.ResultsThe precuneus rTMS not only enhanced episodic memory in SCD, but also improved multiple cognitive domains in MCI. Post-rTMS intervention, decreased VMHC values in the lingual cortex, middle occipital gyrus, putamen, and fusiform gyrus were observed in SCD, and an increased VMHC value in the postcentral gyrus along with reduced VMHC value in the cerebellum and putamen in MCI. After intervention, more brain regions show decreased FC in SCD and MCI patients, suggesting that precuneus rTMS may protect cerebral cortical plasticity by reducing excessive functional compensation, and thus improve cognitive function. The SEM indicated that the corpus callosum serves as the structural foundation for rTMS regulation of interhemispheric FC to further improve cognitive function.Conclusion10 Hz rTMS in the bilateral precuneus could be a promising strategy to improve cognitive function in patients with SCD and MCI. Our study implies that improvements in cognition brought about by precuneus rTMS may result from the remodeling of interhemispheric FC, with the corpus callosum possibly acting as the anatomical basis for functional modulation.

Network pharmacology and in vivo studies reveal the neuroprotective effects of paeoniflorin on Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease that has still not been effectively treated. Paeoniflorin is a traditional Chinese medicine with potential neuroprotective effects against brain injury; however, the beneficial effects and mechanisms of action in AD have not been clarified. We aimed to explore the mechanisms of action of paeoniflorin in AD using network pharmacology and experimental validation. Network pharmacology analysis revealed 30 candidate targets through the intersection of the targets of paeoniflorin and related genes in AD, which were mainly enriched in oxidative stress and inflammation. Moreover, key targets of paeoniflorin against AD, namely Nrf2 (encoded by NFE2L2) and TLR4, were screened and found to be closely related to oxidative stress and inflammation. Subsequent in vivo experiments revealed that paeoniflorin treatment improved the cognition of APP/PS1 mice by ameliorating oxidative stress and neuroinflammation, which were associated with the upregulation of Nrf2 and HO1, and the downregulation of TLR4. Collectively, the present study demonstrates that paeoniflorin alleviates cognitive impairment in AD by regulating oxidative stress and neuroinflammation, and that Nrf2, HO1, and TLR4 could be key targets.

DeepGAMI: deep biologically guided auxiliary learning for multimodal integration and imputation to improve genotype–phenotype prediction

BackgroundGenotypes are strongly associated with disease phenotypes, particularly in brain disorders. However, the molecular and cellular mechanisms behind this association remain elusive. With emerging multimodal data for these mechanisms, machine learning methods can be applied for phenotype prediction at different scales, but due to the black-box nature of machine learning, integrating these modalities and interpreting biological mechanisms can be challenging. Additionally, the partial availability of these multimodal data presents a challenge in developing these predictive models.MethodTo address these challenges, we developed DeepGAMI, an interpretable neural network model to improve genotype–phenotype prediction from multimodal data. DeepGAMI leverages functional genomic information, such as eQTLs and gene regulation, to guide neural network connections. Additionally, it includes an auxiliary learning layer for cross-modal imputation allowing the imputation of latent features of missing modalities and thus predicting phenotypes from a single modality. Finally, DeepGAMI uses integrated gradient to prioritize multimodal features for various phenotypes.ResultsWe applied DeepGAMI to several multimodal datasets including genotype and bulk and cell-type gene expression data in brain diseases, and gene expression and electrophysiology data of mouse neuronal cells. Using cross-validation and independent validation, DeepGAMI outperformed existing methods for classifying disease types, and cellular and clinical phenotypes, even using single modalities (e.g., AUC score of 0.79 for Schizophrenia and 0.73 for cognitive impairment in Alzheimer’s disease).ConclusionWe demonstrated that DeepGAMI improves phenotype prediction and prioritizes phenotypic features and networks in multiple multimodal datasets in complex brains and brain diseases. Also, it prioritized disease-associated variants, genes, and regulatory networks linked to different phenotypes, providing novel insights into the interpretation of gene regulatory mechanisms. DeepGAMI is open-source and available for general use.

The Pathogenesis in Alzheimer's Disease: TREM2 as a Potential Target.

Alzheimer's disease (AD) is ranked as the third-most expensive illness and sixth leading cause of mortality. It is associated with the deposition of extracellular amyloid-β (Aβ) in neural plaques (NPs), as well as intracellular hyperphosphorylated tau proteins that form neurofibrillary tangles (NFTs). As a new target in regulating neuroinflammation in AD, triggering receptor expressed on myeloid cells 2 (TREM2) is highly and exclusively expressed on the microglial surface. TREM2 interacts with adaptor protein DAP12 to initiate signal pathways that mainly dominant microglia phenotype and phagocytosis mobility. Furthermore, TREM2 gene mutations confer increased AD risk, and TREM2 deficiency exhibits more dendritic spine loss around neural plaques. Mechanisms for regulating TREM2 to alleviate AD has evolved as an area of AD research in recent years. Current medications targeting Aβ or tau proteins are unable to reverse AD progression. Emerging evidence implicating neuroinflammation may provide novel insights, as early microglia-related inflammation can be induced decades prior to the commencement of AD-related cognitive damage. Physical exercise can exert a neuroprotective effect over the course of AD progression. This review aims to (1) summarize the pathogenesis of AD and recent updates in the field, (2) assess the concept that AD cognitive impairment is closely correlated with microglia-related inflammation, and (3) review TREM2 functions and its role between exercise and AD, which is likely to be an ideal candidate target.

Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density

Alzheimer’s disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer’s disease has been associated with the localization of the microtubule-associated protein Tau at the postsynapse. However, the correlation between Tau at the postsynapse and synaptic dysfunction remains unclear. Here, we show that Tau arrests liquid-like droplets formed by the four postsynaptic density proteins PSD-95, GKAP, Shank, Homer in solution, as well as NMDA (N-methyl-D-aspartate)-receptor-associated protein clusters on synthetic membranes. Tau-mediated condensate/cluster arrest critically depends on the binding of multiple interaction motifs of Tau to a canonical GMP-binding pocket in the guanylate kinase domain of PSD-95. We further reveal that competitive binding of a high-affinity phosphorylated peptide to PSD-95 rescues the diffusional dynamics of an NMDA truncated construct, which contains the last five amino acids of the NMDA receptor subunit NR2B fused to the C-terminus of the tetrameric GCN4 coiled-coil domain, in postsynaptic density-like condensates/clusters. Taken together, our findings propose a molecular mechanism where Tau modulates the dynamic properties of the postsynaptic density.

Insights to develop tau‐directed therapeutics to protect the synaptic integrity for tauopathies

AbstractTauopathy is characterized by the abnormal aggregation of tau proteins. In order to develop drugs for tauopathies, a variety of different therapeutic strategies have been investigated. Synapse loss is a hallmark of tauopathies and is reportedly related to cognitive impairment in Alzheimer's disease as well. Emerging evidence suggests that pathogenic tau species are linked to synaptic dysfunction and synapse loss in tauopathies. As such, a potential therapeutic approach to ameliorate synaptic dysfunction and counteract synaptic loss due to pathogenic tau holds promise. This review highlights the pathological links between tau pathology and synaptic integrity and current efforts to develop therapeutics rescuing synaptic dysfunction for tauopathies, which will help to understand the association between tau and synapses and develop disease‐modifying drugs for tauopathies.

"The Neuroprotective Effect of SENYDEM®: A New Therapeutic Approach for the Management of Cognitive Impairment in Alzheimer’s Disease"

"The Neuroprotective Effect of SENYDEM®: A New Therapeutic Approach for the Management of Cognitive Impairment in Alzheimer’s Disease"

The Expression of Major Facilitator Superfamily Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is Altered in the Retinas of a 5xFAD Mouse Model of Alzheimer's Disease.

Cerebral amyloid angiopathy (CAA) is characterized by amyloid β (Aβ) accumulation in the blood vessels and is associated with cognitive impairment in Alzheimer's disease (AD). The increased accumulation of Aβ is also present in the retinal blood vessels and a significant correlation between retinal and brain amyloid deposition was demonstrated in living patients and animal AD models. The Aβ accumulation in the retinal blood vessels can be the result of impaired transcytosis and/or the dysfunctional ocular glymphatic system in AD and during aging. We analyzed the changes in the mRNA and protein expression of major facilitator superfamily domain-containing protein2a (Mfsd2a), the major regulator of transcytosis, and of Aquaporin4 (Aqp4), the key player implicated in the functioning of the glymphatic system, in the retinas of 4- and 12-month-old WT and 5xFAD female mice. A strong decrease in the Mfsd2a mRNA and protein expression was observed in the 4 M and 12 M 5xFAD and 12 M WT retinas. The increase in the expression of srebp1-c could be at least partially responsible for the Mfsd2a decrease in the 4 M 5xFAD retinas. The decrease in the pericyte (CD13+) coverage of retinal blood vessels in the 4 M and 12 M 5xFAD retinas and in the 12 M WT retinas suggests that pericyte loss could be associated with the Mfsd2a downregulation in these experimental groups. The observed increase in Aqp4 expression in 4 M and 12 M 5xFAD and 12 M WT retinas accompanied by the decreased perivascular Aqp4 expression is indicative of the impaired glymphatic system. The findings in this study reveal the impaired Mfsd2a and Aqp4 expression and Aqp4 perivascular mislocalization in retinal blood vessels during physiological (WT) and pathological (5xFAD) aging, indicating their importance as putative targets for the development of new treatments that can improve the regulation of transcytosis or the function of the glymphatic system.

Exposure to Polystyrene Microplastics Promotes the Progression of Cognitive Impairment in Alzheimer's Disease: Association with Induction of Microglial Pyroptosis.

We focused on investigating the effects and mechanisms of polystyrene (PS) microplastics in Alzheimer's disease (AD). PS could promote the cognitive impairment in mice and antagonize the action of PS. Meanwhile, it could promote microglial pyroptosis and aggravate neuroinflammation. In vitro results also showed that PS induced pyroptosis of BV2 and RAW264.7, after GSDMD silencing, such pyroptosis was inhibited. Our study found that PS aggravated neuroinflammation by inducing microglial pyroptosis, thereby promoting the progression of cognitive impairment in AD. This finding offers new support and reference for the induction of AD progression by environmental factors.

Ternary Heterojunction Graphitic Carbon Nitride/Cupric Sulfide/Titanium Dioxide Photoelectrochemical Sensor for Sesamol Quantification and Antioxidant Synergism.

Sesamol (SM) is a potent natural antioxidant that can quench free radicals and modulate the cholinergic system in the brain, thereby ameliorating memory and cognitive impairment in Alzheimer's disease patients. Moreover, the total antioxidant capacity can be amplified by synergistic interactions between different antioxidants. Here, we constructed a ternary heterojunction graphitic carbon nitride/cupric sulfide/titanium dioxide (g-C3N4/CuS/TiO2) photoelectrochemical (PEC) sensor for the quantification of SM and its synergistic interactions with other antioxidants. Crucially, the Schottky barrier in ternary semiconductors considerably enhances electron transfer. The PEC sensor showed a wide linear range for SM detection, ranging from 2 to 1277 μmol L-1, and had a limit of detection of 1.8 μmol L-1. Remarkably, this sensing platform could evaluate the synergism between SM and five typical lipid-soluble antioxidants: tert-butyl hydroquinone, vitamin E, butyl hydroxyanisole, propyl gallate, and butylated hydroxytoluene. Owing to its low redox potential, SM could reduce antioxidant radicals and promote their regeneration, which increased the overall antioxidant performance. The g-C3N4/CuS/TiO2 PEC sensor exhibited high sensitivity, satisfactory selectivity, and stability, and was successfully applied for SM determination in both soybean and peanut oils. The findings of this study provide guidance for the development of nutritional foods, nutrition analysis, and the treatment of diseases caused by free radicals.