Catechins, a class of phytochemicals found in various fruits and tea leaves, have garnered attention for their diverse health-promoting properties, including their potential in combating neurodegenerative diseases. Among these catechins, (-)-epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, has emerged as a promising therapeutic agent due to its potent antioxidant and anti-inflammatory effects. Chronic neuroinflammation and oxidative stress are key pathological mechanisms in neurodegenerative diseases such as Alzheimer\'s disease (AD) and Parkinson\'s disease (PD). EGCG has neuroprotective efficacy due to scavenging free radicals, reducing oxidative stress and attenuating neuroinflammatory processes. This review discusses the molecular mechanisms of EGCG\'s anti-oxidative stress and chronic neuroinflammation, emphasizing its effects on autoimmune responses, neuroimmune system interactions, and focusing on the related effects on AD and PD. By elucidating EGCG\'s mechanisms of action and its impact on neurodegenerative processes, this review underscores the potential of EGCG as a therapeutic intervention for AD, PD, and possibly other neurodegenerative diseases. Overall, EGCG emerges as a promising natural compound for combating chronic neuroinflammation and oxidative stress, offering novel avenues for neuroprotective strategies in the treatment of neurodegenerative disorders.

Game theory-inspired deep learning using a generative adversarial network provides an environment to competitively interact and accomplish a goal. In the context of medical imaging, most work has focused on achieving single tasks such as improving image resolution, segmenting images, and correcting motion artifacts. We developed a dual-objective adversarial learning framework that simultaneously 1) reconstructs higher quality brain magnetic resonance images (MRIs) that 2) retain disease-specific imaging features critical for predicting progression from mild cognitive impairment (MCI) to Alzheimer\'s disease (AD). We obtained 3-Tesla, T1-weighted brain MRIs of participants from the Alzheimer\'s Disease Neuroimaging Initiative (ADNI, N=342) and the National Alzheimer\'s Coordinating Center (NACC, N = 190) datasets. We simulated MRIs with missing data by removing 50% of sagittal slices from the original scans (i.e., diced scans). The generator was trained to reconstruct brain MRIs using the diced scans as input. We introduced a classifier into the GAN architecture to discriminate between stable (i.e., sMCI) and progressive MCI (i.e., pMCI) based on the generated images to facilitate encoding of disease-related information during reconstruction. The framework was trained using ADNI data and externally validated on NACC data. In the NACC cohort, generated images had better image quality than the diced scans (Structural similarity (SSIM) index: 0.553 ± 0.116 versus 0.348 ± 0.108). Furthermore, a classifier utilizing the generated images distinguished pMCI from sMCI more accurately than with the diced scans (F1-score: 0.634 ± 0.019 versus 0.573 ± 0.028). Competitive deep learning has potential to facilitate disease-oriented image reconstruction in those at risk of developing Alzheimer\'s disease.

UNASSIGNED: Human epidemiological studies suggest that heavy alcohol consumption may lead to earlier onset of Alzheimer\'s Disease (AD), especially in individuals with a genetic predisposition for AD. Alcohol-related brain damage (ARBD) during a critical developmental timepoint, such as adolescence, interacts with AD-related pathologies to accelerate disease progression later in life. The current study investigates if voluntary exercise in mid-adulthood can recover memory deficits caused by the interactions between adolescence ethanol exposure and AD-transgenes.
UNASSIGNED: Male and female TgF344-AD and wildtype F344 rats were exposed to an intragastric gavage of water (control) or 5 g/kg of 20% ethanol (adolescent intermittent ethanol; AIE) for a 2 day on/off schedule throughout adolescence (PD27-57). At 6 months old, rats either remained in their home cage (stationary) or were placed in a voluntary wheel running apparatus for 4 weeks and then underwent several behavioral tests. The number of cholinergic neurons in the basal forebrain and measure of neurogenesis in the hippocampus were assessed.
UNASSIGNED: Voluntary wheel running recovers spatial working memory deficits selectively in female TgF344-AD rats exposed to AIE and improves pattern separation impairment seen in control TgF344-AD female rats. There were sex-dependent effects on brain pathology: Exercise improves the integration of recently born neurons in AIE-exposed TgF344-AD female rats. Exercise led to a decrease in amyloid burden in the hippocampus and entorhinal cortex, but only in male AIE-exposed TgF344-AD rats. Although the number of basal forebrain cholinergic neurons was not affected by AD-transgenes in either sex, AIE did reduce the number of basal forebrain cholinergic neurons in female rats.
UNASSIGNED: These data provide support that even after symptom onset, AIE and AD related cognitive decline and associated neuropathologies can be rescued with exercise in unique sex-specific ways.

In recent years, brain imaging genomics has advanced significantly in revealing underlying pathological mechanisms of Alzheimer\'s disease (AD) and providing early diagnosis. In this paper, we present a framework for diagnosing AD that integrates magnetic resonance imaging (fMRI) genetic preprocessing, feature selection, and a support vector machine (SVM) model. In particular, a novel sand cat swarm optimization (SCSO) algorithm, named SS-SCSO, which integrates the spiral search strategy and alert mechanism from the sparrow search algorithm, is proposed to optimize the SVM parameters. The optimization efficacy of the SS-SCSO algorithm is evaluated using CEC2017 benchmark functions, with results compared with other metaheuristic algorithms (MAs). The proposed SS-SCSO-SVM framework has been effectively employed to classify different stages of cognitive impairment in Alzheimer\'s Disease using imaging genetic datasets from the Alzheimer\'s Disease Neuroimaging Initiative. It has demonstrated excellent classification accuracies for four typical cases, including AD, early mild cognitive impairment, late mild cognitive impairment, and healthy control. Furthermore, experiment results indicate that the SS-SCSO-SVM algorithm has a stronger exploration capability for diagnosing AD compared to other well-established MAs and machine learning techniques.

CD2-Associated protein (CD2AP) is a candidate susceptibility gene for Alzheimer\'s disease, but its role in the mammalian central nervous system remains largely unknown. We show that CD2AP protein is broadly expressed in the adult mouse brain, including within cortical and hippocampal neurons, where it is detected at pre-synaptic terminals. Deletion of Cd2ap altered dendritic branching and spine density, and impaired ubiquitin-proteasome system activity. Moreover, in mice harboring either one or two copies of a germline Cd2ap null allele, we noted increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release. Whereas conditional Cd2ap knockout in the brain revealed no gross behavioral deficits in either 3.5- or 12-month-old mice, Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning using a touchscreen task. Based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function. Overall, our results reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity, and inform our understanding of possible cell-type specific mechanisms in Alzheimer\'s Disease.

BACKGROUND: The accumulation of beta-amyloid peptide (Aβ) in the forebrain leads to cognitive dysfunction and neurodegeneration in Alzheimer\'s disease. Studies have shown that individuals with a consistently cognitively active lifestyle are less vulnerable to Aβ toxicity. Recent research has demonstrated that intrahippocampal Aβ can impact catecholaminergic release and spatial memory. Interestingly, exposure to novelty stimuli has been found to stimulate the release of catecholamines in the hippocampus. However, it remains uncertain whether repeated enhancing catecholamine activity can effectively alleviate cognitive impairment in individuals with Alzheimer\'s disease.
OBJECTIVE: Our primary aim was to investigate whether repeated exposure to novelty could enable cognitive resilience against Aβ. This protection could be achieved by modulating catecholaminergic activity within the hippocampus.
METHODS: To investigate this hypothesis, we subjected mice to three different conditions-standard housing (SH), repeated novelty (Nov), or daily social interaction (Soc) for one month. We then infused saline solution (SS) or Aβ (Aβ1-42) oligomers intrahippocampally and measured spatial memory retrieval in a Morris Water Maze (MWM). Stereological analysis and extracellular baseline dopamine levels using in vivo microdialysis were assessed in independent groups of mice.
RESULTS: The mice that received Aβ1-42 intrahippocampal infusions and remained in SH or Soc conditions showed impaired spatial memory retrieval. In contrast, animals subjected to the Nov protocol demonstrated remarkable resilience, showing strong spatial memory expression even after Aβ1-42 intrahippocampal infusion. The stereological analysis indicated that the Aβ1-42 infusion reduced the tyrosine hydroxylase axonal length in SH or Soc mice compared to the Nov group. Accordingly, the hippocampal extracellular dopamine levels increased significantly in the Nov groups.
CONCLUSIONS: These compelling results demonstrate the potential for repeated novelty exposure to strengthen the dopaminergic system and mitigate the toxic effects of Aβ1-42. They also highlight new and promising therapeutic avenues for treating and preventing AD, especially in its early stages.

Preclinical and clinical studies have indicated that compromised blood-brain barrier (BBB) function contributes to Alzheimer\'s disease (AD) pathology. BBB breakdown ranged from mild disruption of tight junctions (TJs) with increased BBB permeability to chronic integrity loss, affecting transport across the BBB, reducing brain perfusion, and triggering inflammatory responses. We recently developed a high-throughput screening (HTS) assay to identify hit compounds that enhance the function of a cell-based BBB model. The HTS screen identified (S,E)-2-acetyl-6-[3-(4\'-fluorobiphenyl-4-yl)acryloyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo-[b,d]furan-1(9bH)-one (4-FPBUA), a semisynthetic analogue of naturally occurring usnic acid, which protected the in vitro model against Aβ toxicity. Usnic acid is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton that is commonly found in lichenized fungi of the genera Usnea. In this study, we aimed to evaluate the effect of 4-FPBUA in vitro on the cell-based BBB model function and its in vivo ability to rectify BBB function and reduce brain Aβ in two AD mouse models, namely, 5xFAD and TgSwDI. Our findings demonstrated that 4-FPBUA enhanced cell-based BBB function, increased Aβ transport across the monolayer, and reversed BBB breakdown in vivo by enhancing autophagy as an mTOR inhibitor. Induced autophagy was associated with a significant reduction in Aβ accumulation and related pathologies and improved memory function. These results underscore the potential of 4-FPBUA as a candidate for further preclinical exploration to better understand its mechanisms of action and to optimize dosing strategies. Continued research may also elucidate additional pathways through which 4-FPBUA contributed to the amelioration of BBB dysfunction in AD. Collectively, our findings supported the development of 4-FPBUA as a therapeutic agent against AD.

Alzheimer\'s disease (AD) is the most common neurodegenerative disease in the central nervous system, characterized by memory and cognitive dysfunction. Acupuncture is an effective means to alleviate the symptoms of AD. Recent studies have shown that microglia play an important role in the occurrence and development of AD. Acupuncture can regulate the activity of microglia, inhibit neuroinflammation, regulate phagocytosis, and clear Aβ Pathological products such as plaque can protect nerve cells and improve cognitive function in AD patients. This article summarizes the relationship between microglia and AD, as well as the research progress in the mechanism of acupuncture regulating microglia in the treatment of AD. The mechanism of acupuncture regulating microglia in the treatment of AD is mainly reviewed from two aspects: inhibiting neuroinflammatory activity and regulating phagocytic function.

UNASSIGNED: The relationships between the feeding rhythm, sleep and cognition in Alzheimer\'s disease (AD) are incompletely understood, but meal time could provide an easy-to-implement method of curtailing disease-associated disruptions in sleep and cognition. Furthermore, known sex differences in AD incidence could relate to sex differences in circadian rhythm/sleep/cognition interactions.
UNASSIGNED: The 5xFAD transgenic mouse model of AD and non-transgenic wild-type controls were studied. Both female and male mice were used. Food access was restricted each day to either the 12-h light phase (light-fed groups) or the 12-h dark phase (dark-fed groups). Sleep (electroencephalographic/electromyographic) recording and cognitive behavior measures were collected.
UNASSIGNED: The 5xFAD genotype reduces NREM and REM as well as the number of sleep spindles. In wild-type mice, light-fed groups had disrupted vigilance state amounts, characteristics, and rhythms relative to dark-fed groups. These feeding time differences were reduced in 5xFAD mice. Sex modulates these effects. 5xFAD mice display poorer spatial memory that, in female mice, is curtailed by dark phase feeding. Similarly, female 5xFAD mice have decreased anxiety-associated behavior. These emotional and cognitive measures are correlated with REM amount.
UNASSIGNED: Our study demonstrates that the timing of feeding can alter many aspects of wake, NREM and REM. Unexpectedly, 5xFAD mice are less sensitive to these feeding time effects. 5xFAD mice demonstrate deficits in cognition which are correlated with REM, suggesting that this circadian-timed aspect of sleep may link feeding time and cognition. Sex plays an important role in regulating the impact of feeding time on sleep and cognition in both wild-type and 5xFAD mice, with females showing a greater cognitive response to feeding time than males.

UNASSIGNED: Several studies have revealed that Epstein-Barr virus (EBV) infection raised the likelihood of developing Alzheimer\'s disease (AD) via infecting B lymphocytes. The purpose of the current investigation was to assess the possible association between EBV infection and AD.
UNASSIGNED: The microarray datasets GSE49628, GSE126379, GSE122063, and GSE132903 were utilized to extract DEGs by using the GEO2R tool of the GEO platform. The STRING tool was used to determine the interaction between the DEGs, and Cytoscape was used to visualize the results. The DEGs that were found underwent function analysis, including pathway and GO, using the DAVID 2021 and ClueGo/CluePedia. By using MNC, MCC, Degree, and Radiality of cytoHubba, we identified seven common key genes. Gene co-expression analysis was performed through the GeneMANIA web tool. Furthermore, expression analysis of key genes was performed through GTEx software, which have been identified in various human brain regions. The miRNA-gene interaction was performed through the miRNet v 2.0 tool. DsigDB on the Enrichr platform was utilized to extract therapeutic drugs connected to key genes.
UNASSIGNED: In GEO2R analysis of datasets with |log2FC|≥ 0.5 and p-value <0.05, 8386, 10,434, 7408, and 759 genes were identified. A total of 141 common DEGs were identified by combining the extracted genes of different datasets. A total of 141 nodes and 207 edges were found during the PPI analysis. The DEG GO analysis with substantial alterations disclosed that they are associated to molecular functions and biological processes, such as positive regulation of neuron death, autophagy regulation of mitochondrion, response of cell to insulin stimulus, calcium signaling regulation, organelle transport along microtubules, protein kinase activity, and phosphoserine binding. Kyoto Encyclopedia of Genes and Genomes analysis discovered the correlation between the DEGs in pathways of neurodegeneration: multiple disease, cell cycle, and cGMP-PKG signaling pathway. Finally, YWHAH, YWHAG, YWHAB, YWHAZ, MAP2K1, PPP2CA, and TUBB genes were identified that are strongly linked to EBV and AD. Three miRNAs, i.e., hsa-mir-15a-5p, hsa-let-7a-5p, and hsa-mir-7-5p, were identified to regulate most of hub genes that are associated with EBV and AD. Further top 10 significant therapeutic drugs were predicted.
UNASSIGNED: We have discovered new biomarkers and therapeutic targets for AD, as well as the possible biological mechanisms whereby infection with EBV may be involved in AD susceptibility for the first time.