Alzheimer's Disease Related Genes Research Articles

Understanding perspectives and research trends in Down syndrome neuropathogenesis: A bibliometric analysis.

Down syndrome (DS), characterised by compromised brain development and intellectual challenges, often manifests Alzheimer's disease (AD) -like symptoms. Utilising the Web of Science Core Collection (WOSCC) database from January 1, 2000, to July 31, 2023, we conducted a comprehensive bibliometric analysis using VOSviewer, CiteSpace, and the R package "bibliometrix." Analyses included co-authorship, co-citation, co-occurrence, cooperative network, reference, and keyword burst citation. Analysing 5,082 papers, the U.S. demonstrated prominence with the highest number of research organisations and citations. Keyword analysis revealed promising research areas, including "Alzheimer's disease," "development," "inflammation," and "neurogenesis". This 22-year survey of the brain with trisomy 21 research unveils key trends, contributors, and focal areas in DS neuropathogenesis. Notably, Alzheimer 's-related genes and proteins play a pervasive role in DS neuropathological processes across patients' lifespans. The study contributes foundational knowledge for advancing research and care in the DS neuropathogenesis domain.

Neocortical cholinergic pathology after neonatal brain injury is increased by Alzheimer's disease-related genes in mice

Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aβ plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aβ deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

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.

Synthesis of novel hybrids of 1,2,3-triazoles-hydrazone: targeting cholinesterases and Alzheimer's related genes.

Aim: A new series of 1,2,3-triazole-hydrazone derivatives were developed to evaluate their anti-Alzheimer's activity. Materials & methods: All compounds were screened toward cholinesterases via the modified Ellman's method. The toxicity assay on SH-SY5Y cells was performed using the MTT assay, and the expression levels of GSK-3α, GSK-3β, DYRK1 and CDK5 were assessed in the presence of compounds 6m and 6p.Results:6m and 6p; acting as mixed-type inhibitors, exhibited promising acetylcholinesterase and butyrylcholinesterase inhibitory activity, respectively. 6m demonstrated no toxicity under tested concentrations on the SH-SY5Y cells and positively impacted neurodegenerative pathways. Notably, 6m displayed a significant downregulation in mRNA levels of GSK-3α, GSK-3β and CDK5.Conclusion: The target compounds could be considered in developing anti-Alzheimer's diseaseagents.

Gene Co-Expression Analysis of Multiple Brain Tissues Reveals Correlation of FAM222A Expression with Multiple Alzheimer's Disease-Related Genes.

Alzheimer's disease (AD) is the most common form of dementia in the elderly marked by central nervous system (CNS) neuronal loss and amyloid plaques. FAM222A, encoding an amyloid plaque core protein, is an AD brain atrophy susceptibility gene that mediates amyloid-β aggregation. However, the expression interplay between FAM222A and other AD-related pathway genes is unclear. Our goal was to study FAM222A's whole-genome co-expression profile in multiple tissues and investigate its interplay with other AD-related genes. We analyzed gene expression correlations in Genotype-Tissue Expression (GTEx) tissues to identify FAM222A co-expressed genes and performed functional enrichment analysis on identified genes in CNS system. Genome-wide gene expression profiling identified 673 genes significantly correlated with FAM222A (p < 2.5×10-6) in 48 human tissues, including 298 from 13 CNS tissues. Functional enrichment analysis revealed that FAM222A co-expressed CNS genes were enriched in multiple AD-related pathways. Gene co-expression network analysis for identified genes in each brain region predicted other disease associated genes with similar biological function. Furthermore, co-expression of 25 out of 31 AD-related pathways genes with FAM222A was replicated in brain samples from 107 aged subjects from the Aging, Dementia and TBI Study. This gene co-expression study identified multiple AD-related genes that are associated with FAM222A, indicating that FAM222A and AD-associated genes can be active simultaneously in similar biological processes, providing evidence that supports the association of FAM222A with AD.

Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons.

Alzheimer's disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. To investigate the potential therapeutic benefit of sildenafil on AD. We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil's mechanism-of-action. We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32- 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49- 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.

Prediction of Alzheimer's Disease Based on 3D Genome Selected circRNA.

Alzheimer's disease (AD) is a neurodegenerative disease and there is by far no effective treatment for it, especially in its late stage. Circular RNAs (circRNAs), known as a class of non-coding RNAs are widely observed in eukaryotic transcriptomes, and are reported to play an important role in neurodegenerative diseases including AD. circRNAs usually act as microRNA (miRNA) inhibitors or «sponges» to regulate the function of miRNAs, leading to subsequent changes in protein activities and functions. Accumulating evidence indicates that circRNAs can serve as potential biomarker in AD early prediction. The functional roles of circRNAs are very versatile including miRNAs binding - thus affecting downstream gene expression, generating abnormally translated protein peptides, and affecting epigenetic modifications which subsequently affect AD related gene expressions. Therefore, identifying AD-related circRNAs can contribute to AD early diagnosis and intervention. In this work, we collected and curated an AD-related circRNA dataset; by exploring the circRNAs' corresponding DNA loci distribution in chromatin 3D conformation (3D genome) and utilize the such 3D genome information, we were able to selected a concise yet predictively effective circRNA panel, based on which, significantly better AD prediction machine learning models were achieved.

Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer's agents.

Alzheimer's disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults. Pathogenic factors, such as oxidative stress, an increase in acetylcholinesterase activity, mitochondrial dysfunction, genotoxicity, and neuroinflammation are present in this syndrome, which leads to neurodegeneration. Neurodegenerative pathologies such as Alzheimer's disease are considered late-onset diseases caused by the complex combination of genetic, epigenetic, and environmental factors. There are two main types of Alzheimer's disease, known as familial Alzheimer's disease (onset < 65 years) and late-onset or sporadic Alzheimer's disease (onset ≥ 65 years). Patients with familial Alzheimer's disease inherit the disease due to rare mutations on the amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) genes in an autosomal-dominantly fashion with closely 100% penetrance. In contrast, a different picture seems to emerge for sporadic Alzheimer's disease, which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology. Importantly, the fundamental pathophysiological mechanisms driving Alzheimer's disease are interfaced with epigenetic dysregulation. However, the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer's disease or following injury or stroke in humans. In recent years, there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer's disease. Through epigenetic mechanisms, such as DNA methylation, non-coding RNAs, histone modification, and chromatin conformation regulation, natural compounds appear to exert neuroprotective effects. While we do not purport to cover every in this work, we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer's disease-related genes.

Developmental dynamics of the single nucleus regulatory landscape of pig hippocampus.

The hippocampus is a brain region associated with memory, learning and spatial navigation, its aging-related dysfunction is a common sign of Alzheimer's disease. Pig is a good model for human neurodegenerative disease, but our understanding of the regulatory program of the pig hippocampus and its cross-species conservation in humans remains limited. Here, we profiled chromatin accessibility in 33,409 high-quality nuclei and gene expression in 8,122 high-quality nuclei of the pig hippocampus at four postnatal stages. We identified 510,908 accessible chromatin regions (ACRs) in 12 major cell types, among which progenitor cells such as neuroblasts and oligodendrocyte progenitor cells showed a dynamic decrease from early to later developmental stages. We revealed significant enrichment of transposable elements in cell type-specific ACRs, particularly in neuroblasts. We identified oligodendrocytes as the most prominent cell type with the greatest number of genes that showed significant changes during the development. We identified ACRs and key transcription factors underlying the trajectory of neurogenesis (such as POU3F3 and EGR1) and oligodendrocyte differentiation (RXRA and FOXO6). We examined 27 Alzheimer's disease-related genes in our data and found that 15 showed cell type-specific activity (TREM2, RIN3 and CLU), and 15 genes displayed age-associated dynamic activity (BIN1, RABEP1 and APOE). We intersected our data with human genome-wide association study results to detect neurological disease-associated cell types. The present study provides a single nucleus-accessible chromatin landscape of the pig hippocampus at different developmental stages and is helpful for the exploration of pigs as a biomedical model in human neurodegenerative diseases.

Obesity impacts the expression of Alzheimer's disease-related genes: The Framingham Heart Study.

We investigated associations of obesity with the expression of Alzheimer's disease (AD)-related genes in a large community-based cohort. The sample consisted of 5619 participants from the Framingham Heart Study. Obesity metrics included body mass index (BMI) and waist-to-hip ratio (WHR). Gene expression was measured for a set of 74 AD-related genes, derived by integrating genome-wide association study results with functional genomics data. Obesity metrics were associated with the expression of 21 AD-related genes. The strongest associations were observed with CLU, CD2AP, KLC3, and FCER1G. Unique associations were noted with TSPAN14, SLC24A4 for BMI, and ZSCAN21, BCKDK for WHR. After adjustment for cardiovascular risk factors, 13 associations remained significant for BMI and 8 for WHR. Dichotomous obesity metrics exhibited unique associations with EPHX2 for BMI, and with TSPAN14 for WHR. Obesity was associated with AD-related gene expression; these findings shed light on the molecular pathways linking obesity to AD.

Computational prognostic evaluation of Alzheimer's drugs from FDA-approved database through structural conformational dynamics and drug repositioning approaches.

Novel drug design is time consuming and very expensive process having particularly low success rate. To overcome these difficulties, drug repositioning also referred to as drug repurposing approach is being used to predict the possible alternative therapeutic effects of drugs approved by FDA for different diseases. In this study, we designed a computational mechanism-based approach to fetch promising drugs from the pool of FDA approved drugs to screen them for treatment of Alzheimer's disease (AD). The binding interaction patterns and conformations of screened drugs within active region of MAP Kinase Activating Death Domain (MADD) protein were confirmed through molecular docking profiles. The possible associations of selected drugs with AD related genes were predicted by pharmacogenomics analysis and confirmed through data mining. Furthermore, the stability behavior of docked (Drug-MADD) complexes was checked by MD simulations. Taken together, five drugs displayed promising features and can be used as possible therapeutic agents in the treatment of AD after detailed in vitro studies and clinical assessments.

Single-neuron whole genome sequencing identifies increased somatic mutation burden in Alzheimer's disease related genes

Accumulation of somatic mutations in human neurons is associated with aging and neurodegeneration. To shed light on the somatic mutational burden in Alzheimer's disease (AD) neurons and get more insight into the role of somatic mutations in AD pathogenesis, we performed single-neuron whole genome sequencing to detect genome-wide somatic mutations (single nucleotide variants (SNVs) and Indels) in 96 single prefrontal cortex neurons from 8 AD patients and 8 elderly controls. We found that the mutational burden is ∼3000 somatic mutations per neuron genome in elderly subjects. AD patients have increased somatic mutation burden in AD-related annotation categories, including AD risk genes and differentially expressed genes in AD neurons. Mutational signature analysis showed somatic SNVs (sSNVs) primarily caused by aging and oxidative DNA damage processes but no significant difference was detected between AD and controls. Additionally, functional somatic mutations identified in AD patients showed significant enrichment in several AD-related pathways, including AD pathway, Notch-signaling pathway and Calcium-signaling pathway. These findings provide genetic insights into how somatic mutations may alter the function of single neurons and exert their potential roles in the pathogenesis of AD.

The anti-Alzheimer compounds from tempeh oil in LPS-induced neuronal Schwann cells

AbstractTempeh is a traditional fermented Indonesian food from white soybean. Tempe has better nutritional value than non-fermented white soybean. The aim of this study was to extract tempeh oil and analyze the inhibitory potency of Alzheimer-related gene expression in LPS-induced neuronal Schwann cells. Tempeh oil was extracted with Bligh Dyer method and was analyzed with PUFA identification, anticholinesterase activity, antioxidant activity, and quantitative PCR. Tempeh oil had a total yield of 7.14%, and PUFA identification found 8.37% omega-3. The anti-acetylcholinesterase activity showed that tempeh oil 25 µg/mL had the highest activity and 500 µg/mL in anti-butyrylcholinesterase activity. The quantitative PCR showed that tempeh oil had downregulated the gene expression of PSEN1, Gsk3b, cdk5, and TNF. From this study, tempeh oil may have the potential to lower the risk of Alzheimer’s disease by regulating certain gene traits.

In Alzheimer-prone brain regions, metabolism and risk-gene expression are strongly correlated.

Neuroimaging in the preclinical phase of Alzheimer’s disease provides information crucial to early intervention, particularly in people with a high genetic risk. Metabolic network modularity, recently applied to the study of dementia, is increased in Alzheimer’s disease patients compared with controls, but network modularity in cognitively unimpaired elderly with various risks of developing Alzheimer’s disease needs to be determined. Based on their 5-year cognitive progression, we stratified 117 cognitively normal participants (78.3 ± 4.0 years of age, 52 women) into three age-matched groups, each with a different level of risk for Alzheimer’s disease. From their fluorodeoxyglucose PET we constructed metabolic networks, evaluated their modular structures using the Louvain algorithm, and compared them between risk groups. As the risk for Alzheimer’s disease increased, the metabolic connections among brain regions weakened and became more modular, indicating network fragmentation and functional impairment of the brain. We then set out to determine the correlation between regional brain metabolism, particularly in the modules derived from the previous analysis, and the regional expression of Alzheimer-risk genes in the brain, obtained from the Allen Human Brain Atlas. In all risk groups of this elderly population, the regional brain expression of most Alzheimer-risk genes showed a strong correlation with brain metabolism, particularly in the module that corresponded to regions of the brain that are affected earliest and most severely in Alzheimer’s disease. Among the genes, APOE and CD33 showed the strongest negative correlation and SORL1 showed the strongest positive correlation with brain metabolism. The Pearson correlation coefficients remained significant when contrasted against a null-hypothesis distribution of correlation coefficients across the whole transcriptome of 20 736 genes (SORL1: P = 0.0130; CD33, P = 0.0136; APOE: P = 0.0093). The strong regional correlation between Alzheimer-related gene expression in the brain and brain metabolism in older adults highlights the role of brain metabolism in the genesis of dementia.

Discovering Gene Signature Shared by Prostate Cancer and Neurodegenerative Diseases Based on the Bioinformatics Approach.

Background Prostate cancer (PCa) is one of the highest frequent malignant tumors with very complicated pathogenesis. Genes of neurodegenerative diseases can influence tumor progression. But its role in the progression of PCa remains unclear. The purpose of the present academic work was to identify significant genes with poor outcome and their underlying mechanism. Methods The GSE70768, GSE88808, and GSE134051 datasets were downloaded to screen the differentially expressed genes (DEGs). The DEG screening criteria were as follows: P < 0.05 and differential fold change |logFC| ≥ 1. The common DEGs (co-DEGs) of the three datasets were obtained by the Robust Rank Aggregation (RRA) method. Gene Ontology (GO) function annotation and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis were performed using R software. Protein-protein interaction (PPI) network analysis was performed for co-DEGs using STRING to screen critical genes. Differential expression and prognosis of key genes were analyzed by the online tool Gene Expression Profiling Interactive Analysis 2 (GEPIA2). The intersection gene between key genes and neurodegenerative genes was identified by constructing a Venn diagram. Results A total of 263 co-DEGs were identified from the three datasets. GO analysis showed that co-DEGs were mainly involved in muscle contraction and blood circulation regulation. The top ten key genes were ACTG2, APOE, F5, CALD1, MYH11, MYL9, MYLK, TPM1, TPM2, and CALM1. GEPIA2 analysis showed that APOE, MYH11, and MYLK differ dramatically between tumor and normal tissues. These key genes are related to disease-free survival (DFS) in PCa. APOE was the intersection gene between key genes and Alzheimer-related genes. Conclusion The neurodegenerative gene APOE may be a potential prognostic and diagnostic biomarker for PCa.

Participation of Amyloid and Tau Protein in Post-Ischemic Neurodegeneration of the Hippocampus of a Nature Identical to Alzheimer's Disease.

Recent evidence suggests that amyloid and tau protein are of vital importance in post-ischemic death of CA1 pyramidal neurons of the hippocampus. In this review, we summarize protein alterations associated with Alzheimer’s disease and their gene expression (amyloid protein precursor and tau protein) after cerebral ischemia, as well as their roles in post-ischemic hippocampus neurodegeneration. In recent years, multiple studies aimed to elucidate the post-ischemic processes in the development of hippocampus neurodegeneration. Their findings have revealed the dysregulation of genes for amyloid protein precursor, β-secretase, presenilin 1 and 2, tau protein, autophagy, mitophagy, and apoptosis identical in nature to Alzheimer’s disease. Herein, we present the latest data showing that amyloid and tau protein associated with Alzheimer’s disease and their genes play a key role in post-ischemic neurodegeneration of the hippocampus with subsequent development of dementia. Therefore, understanding the underlying process for the development of post-ischemic CA1 area neurodegeneration in the hippocampus in conjunction with Alzheimer’s disease-related proteins and genes will provide the most important therapeutic development goals to date.

Alzheimer-related genes show accelerated evolution

Alzheimerʼs disease (AD) is a neurodegenerative disorder of unknown cause with complex genetic and environmental traits. While AD is extremely prevalent in human elderly, it hardly occurs in non-primate mammals and even non-human-primates develop only an incomplete form of the disease. This specificity of AD to human clearly implies a phylogenetic aspect. Still, the evolutionary dimension of AD pathomechanism remains difficult to prove and has not been established so far. To analyze the evolutionary age and dynamics of AD-associated-genes, we established the AD-associated genome-wide RNA-profile comprising both protein-coding and non-protein-coding transcripts. We than applied a systematic analysis on the conservation of splice-sites as a measure of gene-structure based on multiple alignments across vertebrates of homologs of AD-associated-genes. Here, we show that nearly all AD-associated-genes are evolutionarily old and did not originate later in evolution than not-AD-associated-genes. However, the gene-structures of loci, that exhibit AD-associated changes in their expression, evolve faster than the genome at large. While protein-coding-loci exhibit an enhanced rate of small changes in gene structure, non-coding loci show even much larger changes. The accelerated evolution of AD-associated-genes indicates a more rapid functional adaptation of these genes. In particular AD-associated non-coding-genes play an important, as yet largely unexplored, role in AD. This phylogenetic trait indicates that recent adaptive evolution of human brain is causally involved in basic principles of neurodegeneration. It highlights the necessity for a paradigmatic change of our disease-concepts and to reconsider the appropriateness of current animal-models to develop disease-modifying strategies that can be translated to human.

Intracerebroventricular streptozotocin induces behavioral impairments and increases short-term C3 gene expression in the hippocampus of Wistar rats

A non‑transgenic rat model based on intracerebroventricular injection of streptozotocin (STZ) has been used as an animal model to investigate mechanisms associated to the late onset of sporadic Alzheimer's disease, such as anatomical and behavioral impairments. However, molecular aspects related to gene expression, mainly in the hippocampus, require more investigation. Thus, this study evaluated the early and late cognitive functions and hippocampal gene expression after STZ administration. Male Wistar rats were divided into 4 groups: STZ (injected bilaterally), control group for the early memory function evaluation (1 month after surgery = phase 1, same volume of vehicle), and the same treatment for the late memory function evaluation (4 months after surgery = phase 2). The animals were observed in the elevated plus maze to assess behaviors related to anxiety, risk‑assessment and fear‑related memories. The behavioral tests were followed by brain removal and hippocampal dissection for RNA extraction and qRT‑PCR to assess the expression levels of 4 Alzheimer's disease related genes: Mapt, Apoe, C3 and Ps‑1. Animals from both phases showed increased time percentage and number of entries into the open arms, indicating risk behavior associated with anxiety, and an increased time percentage in the center square for both exposures (re‑test) when compared to the control group, suggesting working memory impairment related to an aversive event. Statistical analyses indicated that the STZ group presented alterations in anxiety, memory and risk assessment responses. Additionally, one month after STZ administration, C3 gene assays revealed an increased expression. Therefore, current data indicate that neuroinflammatory events linked to the expression of pro inflammatory cytokines such as C3 are related to memory, anxiety and decision-making alterations.

Phytol loaded PLGA nanoparticles regulate the expression of Alzheimer's related genes and neuronal apoptosis against amyloid-β induced toxicity in Neuro-2a cells and transgenic Caenorhabditis elegans

Amyloid β (Aβ) induced neurotoxicity has been postulated to initiate synaptic loss and subsequent neuronal degeneration in Alzheimer's disease (AD). The nanoparticles based drug carrier system is considered as a promising therapeutic strategy to combat this incurable disease. It was also found to inhibit cholinesterase activity and apoptosis mediated cell death in Neuro-2a cells. The in vivo study further revealed that the Phytol and Phytol-PLGA NPs (Poly Lactic-co-Glycolic Acid Nanoparticles) was found to increase the lifespan, chemotaxis behavior and decrease Aβ deposition & ROS (Reactive oxygen species) production in transgenic Caenorhabditis elegans models of AD (CL2006, CL4176). Phytol and Phytol-PLGA NPs treatment downregulated the expression of AD associated genes viz Aβ, ace-1 and hsp-4 and upregulated the gene involved in the longevity to nematodes (dnj-14) and it also reduced the expression of Aβ peptide at the protein level. Our results of in vitro and in vivo studies suggest that Phytol and Phytol-PLGA NPs hold promising neuroprotective efficacy and targets multiple neurotoxic mechanisms involved in the AD progression.

Amyloid-β induced neuropathological actions are suppressed by Padina gymnospora (Phaeophyceae) and its active constituent α-bisabolol in Neuro2a cells and transgenic Caenorhabditis elegans Alzheimer's model

The inhibition of Aβ peptide development and aggregation is a hopeful curative approach for the discovery of disease modifying drugs for Alzheimer's disease (AD) treatment. Recent research mainly focuses on the discovery of drugs from marine setting due to their immense therapeutic potential. The present study aims to evaluate the brown macroalga Padina gymnospora and its active constituent α-bisabolol against Aβ25-35 induced neurotoxicity in Neuro2a cells and transgenic Caenorhabditis elegans (CL2006 and CL4176). The results of the in vitro study revealed that the acetone extract of P. gymnospora (ACTPG) and its active constituent α-bisabolol restores the Aβ25-35 induced alteration in the oxidation of intracellular protein and lipids. In addition, ACTPG and α-bisabolol inhibited cholinesterase and β-secretase activity in Neuro2a cells. Moreover, the intracellular reactive oxygen species (ROS) and reactive nitrogen species (RNS) production was reduced by ACTPG and α-bisabolol in Neuro2a cells. The decrease in the expression level of apoptotic proteins such as Bax and caspase-3 in ACTPG and α-bisabolol treated group indicates that the seaweed and its bioactive compound have anti-apoptotic property. Further, the in vivo study revealed that the ACTPG and α-bisabolol exerts neuroprotective effect against Aβ induced proteotoxicity in transgenic C. elegans strains of AD. Moreover it altered the Aβ mediated pathways, lifespan, macromolecular damage and down regulated the AD related gene expression of ace-1, hsp-4 and Aβ, thereby preventing Aβ synthesis. Overall, the outcome of the study signifies the neuroprotective effect of ACTPG and α-bisabolol against Aβ mediated AD pathology.