AD-related Genes Research Articles

Primate-specific 82-kDa choline acetyltransferase attenuates progression of Alzheimer's disease-like pathology in the APPNL-G-F knock-in mouse model.

Alzheimer's disease (AD) is characterized by amyloidosis, neuroinflammation, cholinergic dysfunction and cognitive impairment. In AD, the cholinergic neuronal marker choline acetyltransferase (ChAT) is reduced and the primate-specific nuclear isoform, 82-kDa ChAT, is mislocalized to cytoplasm. Cell-based studies suggest a role for 82-kDa ChAT in regulating expression of AD-related genes with potential reductions in β-amyloid (Aβ) levels. To study this further, we crossed transgenic mice expressing human 82-kDa ChAT with the AD mouse model APPNL-G-F and used molecular techniques and neurobehavioral tests to study the impact of 82-kDa ChAT on AD pathology. These mice had altered expression of genes linked to Aβ clearance and inflammation, and reduced cognitive decline, amyloidosis and gliosis. These effects were inversely related to age and Aβ plaque load and correlated best with 82-kDa ChAT localized to nuclei of neurons. The study suggests a role for 82-kDa ChAT in decreasing AD-like pathology.

The study of Alzheimer's disease risk diagnosis based on natural killer cell marker genes in the multi-omics data.

Alzheimer's disease (AD) is a common neurodegenerative disorder, currently lacking effective early diagnostic methods. However, natural killer (NK) cells may play a potential role in AD pathogenesis. This study aims to identify AD-related feature genes from NK cell markers to construct a diagnostic model and explore their potential biological mechanisms in AD. Single-cell RNA sequencing data was used to identify NK cell markers. A novel feature selection algorithm, adaptive dynamic graph convolutional network (ADGCN), was proposed to extract AD-related feature genes and construct a diagnostic model. Differential, correlation and enrichment analyses were performed to understand the biological mechanisms of these genes. Immune infiltration analysis compared the immune microenvironment between AD and controls. Two regulatory networks explored interactions between feature genes, transcription factors and microRNAs. The association between SNPs and feature genes' expression was examined through expression quantitative trait loci analysis. Differential CpG sites were identified to analyze their association with the NK cell markers' expression. We developed an optimal diagnostic model (ADGCN-XGBoost) with 17 feature genes, demonstrating high diagnostic effectiveness across datasets. These genes were primarily related to macromolecule biosynthesis, cytoplasmic translation biological processes and ribosome pathway, and potentially modulated immune infiltration of AD patients. We predicted 27 target miRNAs and 21 transcription factors influencing these genes. Multimodal analysis identified 57 significant SNP-gene associations and seven CpG-gene pairs. This study proposed a novel feature selection algorithm and developed a diagnostic model based on 17 feature genes, providing new potential biomarkers for AD diagnosis.

Evaluation of Selected Plant Phenolics via Beta-Secretase-1 Inhibition, Molecular Docking, and Gene Expression Related to Alzheimer’s Disease

Background: The goal of the current study was to investigate the inhibitory activity of six phenolic compounds, i.e., rosmarinic acid, gallic acid, oleuropein, epigallocatechin gallate (EGCG), 3-hydroxytyrosol, and quercetin, against β-site amyloid precursor protein cleaving enzyme-1 (BACE1), also known as β-secretase or memapsin 2, which is implicated in the pathogenesis of Alzheimer’s disease (AD). Methods and Results: The inhibitory potential against BACE1, molecular docking simulations, as well as neurotoxicity and the effect on the AD-related gene expression of the selected phenolics were tested. BACE1 inhibitory activity was carried out using the ELISA microplate assay via fluorescence resonance energy transfer (FRET) technology. Molecular docking experiments were performed in the human BACE1 active site (PDB code: 2WJO). Neurotoxicity of the compounds was carried out in SH-SY5Y, a human neuroblastoma cell line, by the Alamar Blue method. A gene expression analysis of the compounds on fourteen genes linked to AD was conducted using the real-time polymerase chain reaction (RT-PCR) method. Rosmarinic acid, EGCG, oleuropein, and quercetin (also used as the reference) were able to inhibit BACE1 with their respective IC50 values 4.06 ± 0.68, 1.62 ± 0.12, 9.87 ± 1.01, and 3.16 ± 0.30 mM. The inhibitory compounds were observed to occupy the non-catalytic site of the BACE1. However, hydrogen bonds were found to be present between rosmarinic acid and EGCG and aspartic amino acid D228 in the catalytic site. Oleuropein and quercetin effectively suppressed the expression of PSEN, APOE, and CLU, which are recognized to be linked to the pathogenesis of AD. Conclusions: The outcomes of the work bring quercetin, EGCG, and rosmarinic acid to the forefront as promising BACE1 inhibitors.

IDEEA: information diffusion model for integrating gene expression and EEG data in identifying Alzheimer’s disease markers

Abstract Understanding the genetic components of Alzheimer’s disease (AD) via transcriptome analysis often necessitates the use of invasive methods. This work focuses on overcoming the difficulties associated with the invasive process of collecting brain tissue samples in order to measure and investigate the transcriptome behavior of AD. Our approach called IDEEA (Information Diffusion model for integrating gene Expression and EEG data in identifying Alzheimer’s disease markers) involves systematically linking two different but complementary modalities: transcriptomics and EEG data. We preprocess these two data types by calculating the spectral and transcriptional sample distances, over 11 brain regions encompassing 6 distinct frequency bands. Subsequently, we employ a genetic algorithm approach to integrate the distinct features of the preprocessed data. Our experimental results show that
IDEEA converges rapidly to local optima gene subsets, in fewer than 250 iterations. Our algorithm identifies novel genes along with genes that have previously been linked to AD. It is also capable of detecting genes with transcription patterns specific to individual EEG bands as well as those with common patterns among bands. In particular, the alpha2 (10-13 Hz) frequency band yielded 8 AD associated genes out of the top 100 most frequently selected genes by our algorithm, with a p-value of
0.05. Our method not only identifies AD-related genes but also genes that interact with AD genes in terms of transcription regulation. We evaluated various aspects of our approach, including the genetic algorithm performance, band-pair association and gene interaction topology. Our approach reveals AD-relevant genes with transcription patterns inferred from EEG alone, across various frequency bands, avoiding the risky brain tissue collection process. This is a significant advancement toward the early identification of AD using non-invasive EEG recordings.

Intravenous chaperone treatment of late-stage Alzheimer´s disease (AD) mouse model affects amyloid plaque load, reactive gliosis and AD-related genes

Treatment strategies that are efficient against established Alzheimer’s disease (AD) are needed. BRICHOS is a molecular chaperone domain that prevents amyloid fibril formation and associated cellular toxicity. In this study, we treated an AD mouse model seven months after pathology onset, using intravenous administration of recombinant human (rh) Bri2 BRICHOS R221E. Two injections of rh Bri2 BRICHOS R221E per week for three months in AD mice reduced amyloid β (Aβ) burden, and mitigated astro- and microgliosis, as determined by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Sequencing of RNA from cortical microglia cells showed that BRICHOS treatment normalized the expression of identified plaque-induced genes in mice and humans, including clusterin and GFAP. Rh Bri2 BRICHOS R221E passed the blood–brain barrier (BBB) in age-matched wild-type mice as efficiently as in the AD mice, but then had no effect on measures of AD-like pathology, and mainly affected the expression of genes that affect cellular shape and movement. These results indicate a potential of rh Bri2 BRICHOS against advanced AD and underscore the ability of BRICHOS to target amyloid-induced pathology.

Identification of cuproptosis-related genes in Alzheimer’s disease based on bioinformatic analysis

ObjectiveTo explore the role of cuproptosis in Alzheimer’s disease (AD).MethodsAn AD-related microarray dataset was downloaded from the Gene Expression Omnibus (GEO) database (GSE140830). Weighted gene co-expression network analysis was used to identify AD-related modular genes. The Venn analysis was performed to obtain module genes associated with apoptosis and cuproptosis. Besides, we conducted an enrichment analysis of overlapped genes and constructed the protein–protein interaction (PPI) network, followed by screening hub genes and those significantly associated with AD were used to construct models of apoptosis and cuproptosis, respectively. Further, receiver operating characteristic (ROC) curve analysis, decision curve analysis (DCA), and subgroup analysis were used to compare the AD prediction performance of two models. Finally, the accuracy and reliability of AD prediction models were verified by GSE26927.ResultsWe obtained 42 module genes related to apoptosis and 9 module genes related to cuproptosis. The enrichment analysis results revealed MAPK signaling pathway as the common signaling pathway of apoptosis- and cuproptosis-related genes. Next, the hub genes associated with apoptosis (TRADD, FADD, BIRC2, and CASP2) and cuproptosis (MAP2K1, SLC31A1, and PDHB) in AD were identified, which were used to construct apoptosis and cuproptosis models to distinguish AD patients from the control group (P < 0.05). The ROC, DCA, and subgroup analysis results showed that apoptosis-related models and cuproptosis-related models had comparable ability in predicting AD. GSE26927 further confirmed that the two models have comparable predictive effects for AD.ConclusionsThe cuproptosis model had a certain performance in predicting AD. Three hub genes (MAP2K1, SLC31A1, and PDHB) closely related to cuproptosis in AD might serve as biomarkers for AD diagnosis and treatment.

A Drug Repositioning Approach Reveals Ergotamine May Be a Potential Drug for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that is the most common form of dementia in the elderly. The drugs currently used to treat AD only have limited effects and are not able to cure the disease. Drug repositioning has increasingly become a promising approach to find potential drugs for diseases like AD. To screen potential drug candidates for AD based on the relationship between risk genes of AD and drugs. We collected the risk genes of AD and retrieved the information of known drugs from DrugBank. Then, the AD-related genes and the targets of each drug were mapped to the human protein-protein interaction network (PPIN) to represent AD and the drugs on the network. The network distances between each drug and AD were calculated to screen the drugs proximal to AD-related genes on PPIN, and the screened drug candidates were further analyzed by molecular docking and molecular dynamics simulations. We compiled a list of 714 genes associated with AD. From 5,833 drugs used for human diseases, we identified 1,044 drugs that could be potentially used to treat AD. Then, amyloid-β (Aβ) protein, the key molecule involved in the pathogenesis of AD was selected as the target to further screen drugs that may inhibit Aβ aggregation by molecular docking. We found that ergotamine and RAF-265 could bind stably with Aβ. In further analysis by molecular dynamics simulations, both drugs exhibited reasonable stability. Our work indicated that ergotamine and RAF-265 may be potential candidates for treating AD.

The downregulation of TREM2 exacerbates toxicity of development and neurobehavior induced by aluminum chloride and nano-alumina in adult zebrafish

To investigate the difference in the development and neurobehavior between aluminum chloride (AlCl3) and nano-alumina (AlNPs) in adult zebrafish and the role of triggering receptor expressed on myeloid cells (TREM2) in this process. Zebrafish embryos were randomly administered with control, negative control, TREM2 knockdown, AlCl3, TREM2 knockdown + AlCl3, AlNPs, and TREM2 knockdown + AlNPs, wherein AlCl3 and AlNPs were 50 mg/L and TREM2 knockdown was achieved by microinjecting lentiviral-containing TREM2 inhibitors into the yolk sac. We assessed development, neurobehavior, histopathology, ultrastructural structure, neurotransmitters (AChE, DA), SOD, genes of TREM2 and neurodevelopment (α1-tubulin, syn2a, mbp), and AD-related proteins and genes. AlCl3 significantly lowered the malformation rate than AlNPs, and further increased rates of malformation and mortality following TREM2 knockdown. The locomotor ability, learning and memory were similar between AlCl3 and AlNPs. TREM2 deficiency further exacerbated their impairment in panic reflex, microglia decrease, and nerve fibers thickening and tangling. AlCl3, rather than AlNPs, significantly elevated AChE activity and p-tau content while decreasing TREM2 and syn2a levels than the control. TREM2 loss further aggravated impairment in the AChE and SOD activity, and psen1 and p-tau levels. Therefore, AlCl3 induces greater developmental toxicity but equivalent neurobehavior toxicity than AlNPs, while their toxicity was intensified by TREM2 deficiency.

Identification of cross-talk pathways and PANoptosis-related genes in periodontitis and Alzheimer's disease by bioinformatics analysis and machine learning.

Periodontitis (PD), a chronic inflammatory disease, is a serious threat to oral health and is one of the risk factors for Alzheimer's disease (AD). A growing body of evidence suggests that the two diseases are closely related. However, current studies have not provided a comprehensive understanding of the common genes and common mechanisms between PD and AD. This study aimed to screen the crosstalk genes of PD and AD and the potential relationship between cross-talk and PANoptosis-related genes. The relationship between core genes and immune cells will be analyzed to provide new targets for clinical treatment. The PD and AD datasets were downloaded from the GEO database and differential expression analysis was performed to obtain DEGs. Overlapping DEGs had cross-talk genes linking PD and OP, and PANoptosis-related genes were obtained from a literature review. Pearson coefficients were used to compute cross-talk and PANoptosis-related gene correlations in the PD and AD datasets. Cross-talk genes were obtained from the intersection of PD and AD-related genes, protein-protein interaction(PPI) networks were constructed and cross-talk genes were identified using the STRING database. The intersection of cross-talk and PANoptosis-related genes was defined as cross-talk-PANoptosis genes. Core genes were screened using ROC analysis and XGBoost. PPI subnetwork, gene-biological process, and gene-pathway networks were constructed based on the core genes. In addition, immune infiltration on the PD and AD datasets was analyzed using the CIBERSORT algorithm. 366 cross-talk genes were overlapping between PD DEGs and AD DEGs. The intersection of cross-talk genes with 109 PANoptosis-related genes was defined as cross-talk-PANoptosis genes. ROC and XGBoost showed that MLKL, DCN, IL1B, and IL18 were more accurate than the other cross-talk-PANoptosis genes in predicting the disease, as well as better in overall characterization. GO and KEGG analyses showed that the four core genes were involved in immunity and inflammation in the organism. Immune infiltration analysis showed that B cells naive, Plasma cells, and T cells gamma delta were significantly differentially expressed in patients with PD and AD compared with the normal group. Finally, 10 drugs associated with core genes were retrieved from the DGIDB database. This study reveals the joint mechanism between PD and AD associated with PANoptosis. Analyzing the four core genes and immune cells may provide new therapeutic directions for the pathogenesis of PD combined with AD.

Exposure to Lead in Drinking Water Causes Cognitive Impairment via an Alzheimer's Disease Gene-Dependent Mechanism in Adult Mice.

Exposure to lead (Pb) is a major public health problem that could occur through contaminated soil, air, food, or water, either during the course of everyday life, or while working in hazardous occupations. Although Pb has long been known as a neurodevelopmental toxicant in children, a recent and growing body of epidemiological research indicates that cumulative, low-level Pb exposure likely drives age-related neurologic dysfunction in adults. Environmental Pb exposure in adulthood has been linked to risk of late-onset Alzheimer's disease (AD) and dementia. Although the biological mechanism underlying this link is unknown, it has been proposed that Pb exposure may increase the risk of AD via altering the expression of AD-related genes and, possibly, by activating the molecular pathways underlying AD-related pathology. We investigated Pb exposure using a line of genetically modified mice with AD-causing knock-in mutations in the amyloid precursor protein and presenilin 1 (APPΔNL/ΔNL x PS1P264L/P264L) that had been crossed with Leprdb/db mice to impart vulnerability to vascular pathology. Our data show that although Pb exposure in adult mice impairs cognitive function, this effect is not related to either an increase in amyloid pathology or to changes in the expression of common AD-related genes. Pb exposure also caused a significant increase in blood pressure, a well known effect of Pb. Interestingly, although the increase in blood pressure was unrelated to genotype, only mice that carried AD-related mutations developed cognitive dysfunction, in spite of showing no significant change in cerebrovascular pathology. These results raise the possibility that the increased risk of dementia associated with Pb exposure in adults may be tied to its subsequent interaction with either pre-existing or developing AD-related neuropathology.

Multi-omics analyses highlight molecular differences between clinical and neuropathological diagnoses in Alzheimer's disease.

Both clinical diagnosis and neuropathological diagnosis are commonly used in literature to categorize individuals as Alzheimer's disease (AD) or non-AD in omics analyses. Whether these diagnostic strategies result in distinct profiles of molecular abnormalities is poorly understood. Here, we analysed one of the most commonly used AD omics datasets in the literature from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort and compared the two diagnosis strategies using brain transcriptome and metabolome by grouping individuals as non-AD and AD according to clinical or neuropathological diagnosis separately. Differentially expressed genes, associated pathways related with AD hallmarks and AD-related genes showed that the categorization based on neuropathological diagnosis more accurately reflects the disease state at the molecular level than the categorization based on clinical diagnosis. We further identified consensus biomarker candidates between the two diagnosis strategies such as 5-hydroxylysine, sphingomyelin and 1-myristoyl-2-palmitoyl-GPC as metabolite biomarkers and sphingolipid metabolism as a pathway biomarker, which could be robust AD biomarkers since they are independent of diagnosis strategies. We also used consensus AD and consensus non-AD individuals between the two diagnostic strategies to train a machine-learning based model, which we used to classify the individuals who were cognitively normal but diagnosed as AD based on neuropathological diagnosis (asymptomatic AD individuals). The majority of these individuals were classified as consensus AD patients for both omics data types. Our study provides a detailed characterization of both diagnostic strategies in terms of the association of the corresponding multi-omics profiles with AD.

Identification of deregulated lncRNAs in Alzheimer's disease: an integrated gene co-expression network analysis of hippocampus and fusiform gyrus RNA-seq datasets.

The deregulation of lncRNAs expression has been associated with neuronal damage in Alzheimer's disease (AD), but how or whether they can influence its onset is still unknown. We investigated 2 RNA-seq datasets consisting, respectively, of the hippocampal and fusiform gyrus transcriptomic profile of AD patients, matched with non-demented controls. We performed a differential expression analysis, a gene correlation network analysis (WGCNA) and a pathway enrichment analysis of two RNA-seq datasets. We found deregulated lncRNAs in common between hippocampus and fusiform gyrus and deregulated gene groups associated to functional pathways related to neurotransmission and memory consolidation. lncRNAs, co-expressed with known AD-related coding genes, were identified from the prioritized modules of both brain regions. We found common deregulated lncRNAs in the AD hippocampus and fusiform gyrus, that could be considered common signatures of AD pathogenesis, providing an important source of information for understanding the molecular changes of AD.

Antigen-specific age-related memory CD8 T cells induce and track Alzheimer’s-like neurodegeneration

Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer's disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aβ/pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-specific memory CD8 T ("hiT") cells act upstream of Aβ/pTau after brain injury. Here, we examine whether hiT cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in our hiT mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. We identify an age-related factor acting upstream of Aβ/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.

High-throughput Virtual Screening- and Molecular Docking-based Prediction for Acetylcholinesterase Inhibitors and Exploring its Mechanisms against Alzheimer’s Disease based on Network Pharmacology

OBJECTIVE This study aimed to identify promising ligands for inhibiting acetylcholinesterase (AChE) activity using virtual screening (VS). METHODS VS was used to identify potential AChE inhibitors from the PubChem database. Ligands with favorable binding pocket interactions were selected. SwissADME and pkCSM tools were used to assess drug-likeness and pharmacokinetic properties. Molecular dynamic (MD) simulations provided insights into binding interactions. Network pharmacology was used to explore interactions between the target molecule and AD-related genes to determine its mechanism of action. RESULTS VS identified promising AChE inhibitor candidates with acridone, carbazole, and xanthone scaffolds. Docking simulations showed strong binding with AChE. These ligands displayed favorable drug-likeness and ADMET properties, with one (M5) lacking predicted hepatotoxicity. MD simulations suggested stable binding of M5 to AChE, potentially affecting both catalytic and peripheral sites, hinting at dual inhibition. M5’s interactions, especially near His440, appeared more favorable than donepezil. Network analysis implicated M5 in targeting multiple pathways in AD, with potential focus on neuroinflammation. CONCLUSIONS This study identified promising AChE inhibitor candidates through virtual screening. Ligand M5 emerged as particularly promising due to its favorable binding characteristics, lack of predicted hepatotoxicity, and potential for targeting multiple pathways in AD. However, further in vitro and in vivo validation is essential for clinical development. KEYWORDS virtual screening, acetylcholinesterase inhibitors, PubChem database, molecular dynamics simulation, gene ontology, KEGG pathways

Exploration of Alzheimer's disease-related gene expression following high-intensity and moderate-intensity exercise interventions

ObjectivesThere are currently 29 genome regions that demonstrate associations with Alzheimer's disease (AD) risk. Regular physical exercise can promote systemic change in gene expression and may modify the risk of cognitive decline and AD. This study is a secondary analysis of a randomised controlled trial and examines the effect of a six-month exercise intervention versus control on AD-related gene expression. DesignSingle-site parallel pilot randomised controlled trial. Methods91 cognitively unimpaired older adults were enrolled in the Intense Physical Activity and Cognition (IPAC) study. Participants were randomised into one of three groups: high-intensity exercise, moderate-intensity exercise, or inactive control for six months. Blood samples were collected prior to, and within two weeks of intervention completion, for later expression analysis of 96 genes. To explore the relationship between changes in gene expression and the intervention groups, an interaction term (“time point × intervention group”) was subsequently used. ResultsThere were no significant differences in gene expression between the three intervention groups at baseline, nor after the intervention. Within groups, five genes were upregulated, seven were downregulated and the remainder remained unchanged. None of the examined genes showed significant change from pre- to post-intervention in the exercise groups compared to the control. ConclusionsExercise does not change AD-related gene expression in cognitively unimpaired older adults. Several gene expression targets have been identified for further study.

Network pharmacology study on fermented soybeans for the prevention of Alzheimer's disease in older individuals.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the disruption of synaptic communication among millions of neurons. Recent research has highlighted the potential therapeutic effectiveness of natural polyphenolic compounds in addressing AD. Soybeans are abundant in polyphenols, and their polyphenolic composition undergoes significant alteration through fermentation by Eurotium cristatum. Through comprehensive database searches, we identified active components within fermented soybean polyphenols and genes associated with AD. Subsequently, we utilized Venn diagrams to analyze the overlap between AD-related genes and these components. Furthermore, we visualized the network between intersecting targets and proteins using Cytoscape software. The anti-AD effects of soybeans were further explored through comprehensive analysis, including protein-protein interaction analysis, pathway enrichment analysis, and molecular docking studies. Our investigation unveiled 6-hydroxydaidzein as a major component of fermented soybean polyphenols, shedding light on its potential therapeutic significance in combating AD. The intersection between target proteins of fermented soybeans and disease-related targets in AD comprised 34 genes. Protein-protein interaction analysis highlighted key potential targets, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glycogen synthase kinase 3 beta (GSK3B), amyloid precursor protein (APP), cyclin-dependent kinase 5 (CDK5), and beta-site APP cleaving enzyme 1 (BACE1). Molecular docking results demonstrated a robust binding effect between major components from fermented soybeans and the aforesaid key targets implicated in AD treatment. These findings suggest that fermented soybeans demonstrate a degree of efficacy and present promising prospects in the prevention of AD.

Profiling the neuroimmune cascade in 3xTg-AD mice exposed to successive mild traumatic brain injuries

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aβ) plaques, gliosis, and neuronal and functional loss. However, a comprehensive study relating acute changes in immune signaling and glial reactivity to neuronal changes and pathological markers after single and repetitive mTBIs is currently lacking. In the current study, we addressed the question of how repeated injuries affect the brain neuroimmune response in the acute phase of injury (< 24 h) by exposing the 3xTg-AD mouse model of tau and Aβ pathology to successive (1x-5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30 min, 4 h, and 24 h after each injury. We used young adult 2–4 month old 3xTg-AD mice to model the effects of rmTBI in the absence of significant tau and Aβ pathology. We identified pronounced sexual dimorphism in this model, with females eliciting more diverse changes after injury compared to males. Specifically, females showed: (1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression and an increase in AD-related genes within 24 h, (2) each injury significantly increased a group of cortical cytokines (IL-1α, IL-1β, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which co-labeled with neurons and correlated with phospho-tau, and (3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and macrophage-associated immune function. Collectively our data suggest that neurons respond to a single injury within 24 h, while other cell types, including astrocytes, transition to inflammatory phenotypes within days of repetitive injury.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model.

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aβ plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aβ clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Epigenetics in Alzheimer's Disease: A Critical Overview.

Epigenetic modifications have been implicated in a number of complex diseases as well as being a hallmark of organismal aging. Several reports have indicated an involvement of these changes in Alzheimer's disease (AD) risk and progression, most likely contributing to the dysregulation of AD-related gene expression measured by DNA methylation studies. Given that DNA methylation is tissue-specific and that AD is a brain disorder, the limitation of these studies is the ability to identify clinically useful biomarkers in a proxy tissue, reflective of the tissue of interest, that would be less invasive, more cost-effective, and easily obtainable. The age-related DNA methylation changes have also been used to develop different generations of epigenetic clocks devoted to measuring the aging in different tissues that sometimes suggests an age acceleration in AD patients. This review critically discusses epigenetic changes and aging measures as potential biomarkers for AD detection, prognosis, and progression. Given that epigenetic alterations are chemically reversible, treatments aiming at reversing these modifications will be also discussed as promising therapeutic strategies for AD.

IL-1β and CXCR4 as Potential Therapeutic Targets for Alzheimer's Disease.

Alzheimer's Disease (AD) is a highly prevalent form of age-related dementia. However, the underlying mechanisms of AD are largely unexplored. In this study, bioinformatics analysis was performed to identify the possible therapeutic targets for AD. The GEO database was used to screen the Differentially Expressed Genes (DEGs). Enrichment analysis, protein-protein interaction network, and LASSO model analyses were successfully performed. Furthermore, an ELISA assay was also conducted to determine the expression of principal genes within the AD and control samples. A total of 416 differentially expressed genes (DEGs) were recognized based on the GSE48350 and GSE28146 datasets. The IL-1β and CXCR4 levels were markedly elevated in the AD samples relative to the control. The IL-1β and CXCR4 genes were identified as principal AD-related genes that can be targeted for anti-AD therapy.