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Synaptosomal MicroRNAs, Synaptic Damage and Cognitive Decline in Alzheimer's Disease

阿尔茨海默病中的突触体 MicroRNA、突触损伤和认知能力下降

基本信息

批准号：
10653353
负责人：
Subodh Kumar
金额：
$ 24.9万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653353
关键词：
Address Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Amyloid beta-Protein Autopsy Behavior Behavioral Biochemical Brain Cognitive Complementary DNA Complex Data Analyses Dendritic Spines Development Disease Progression Functional disorder Genomics Goals Hippocampus (Brain)Impaired cognition In Vitro Knockout Mice Lead Link Mediating Messenger RNA MicroRNAs Microarray Analysis Mitochondria Molecular Mus Neurodegenerative Disorders Neurons Neurotransmitter Receptor Neurotransmitters Outcome Outcome Study Pathogenesis Pathology Physiological Process Property Protein Biosynthesis Proteins Proteomics Publishing Quantitative Reverse Transcriptase PCR RNA Regulation Reporting Research Role Signal Transduction Small RNA Synapses Synaptic Vesicles Synaptic plasticity Synaptosomes Testing Therapeutic Toxic effect Transcript Transgenic Mice Transgenic Organisms United States National Institutes of Health Wild Type Mouse base cognitive function design differential expression disorder control frontal lobe improved inhibitor insight miRNA expression profiling mind control mutant neuronal growth neurotransmission postsynaptic density protein synaptic function tau Proteins tau mutation tau-1 transcriptome sequencing

项目摘要

Title. Synaptosomal MicroRNAs, Synaptic Damage and Cognitive Decline in Alzheimer's Disease Project summary/abstract The purpose of our study is to determine the role of synaptosomal microRNAs (miRNAs) in Alzheimer's disease (AD) progression and pathogenesis. Synapses are the most important compartments of neuron that deliver signals to adjacent neuron and maintain healthy synaptic functions of the brain. Synapse territories are composed of synaptic vesicles, synaptic proteins, mitochondria, neurotransmitters receptors, postsynaptic density protein and localized small RNAs and miRNAs. Recently, several studies identified the miRNAs enrichments at synapse, synaptic vesicles and synaptosomes. However, the role of synapse-associated miRNAs in AD progression is completely unexplored. In the first part of our study, we will identify the synaptosome-specific miRNAs that are deregulated in AD, and further, we will characterize their roles in AD progression and pathogenesis. Synaptosomal fraction will be extracted from frontal cortex region of postmortem brains from AD (n=15) and healthy controls (n=15). Total RNA will be extracted from synaptosomal fraction and processed for miRNA and mRNA sequencing. The deregulated synaptosome- specific miRNAs will be characterized in vitro using miRNA mimics and inhibitor(s) approaches and mutant APP and p-tau cDNA constructs. Impact of synaptosomal miRNAs will be studied against Aβ and p-tau induced toxicities. In second part we will determine the role of synaptosomal miRNAs in Aβ induced synaptic and cognitive dysfunction in AD. The impact of synaptosomal miRNAs will be studied on healthy neurons and AD neurons with Aβ induced toxicities. We will focus on neuronal processing, neuronal growth and network development and synaptic plasticity using APP primary neuronal cultures. Alteration of synaptosomal miRNAs expression and synaptic proteins will be studied with disease progression in APP transgenic (TG) and APP knockout (KO) mice. We will execute the synaptosome-specific miRNAs expression with various cognitive behavioral and biochemical tests in 2-, 6-, 12- and 18-month-old APP TG and APP KO mice lines relative to age-matched TG negative wild-type (WT) mice. And in third part we will study the role of synaptosomal miRNAs in phosphorylated-tau (p-tau) induced synaptic and cognitive dysfunction in AD. The impact of synaptosomal miRNAs will be studied on p-tau induced toxicity in neurons, healthy neurons processing, neuronal growth and network development and synaptic plasticity using tau primary neuronal culture. Alteration of synaptosomal miRNAs and synaptic proteins will be studied with disease progression in Tau TG and Tau KO mice. We will execute the synaptosome-specific miRNAs expression with various cognitive behavioral and biochemical tests in 2-, 6-, 12- and 18-month-old tau TG and KO mice relative to WT mice. Our study outcome will provide the answers for - 1) presence of synaptosomal miRNAs at AD synapse, 2) synaptosome- associated miRNAs linked with Aβ and p-tau pathologies in AD, 3) Overall synapse function, synaptic activity, assessment of therapeutic value of synaptosome-associated miRNAs in AD.

标题。阿尔茨海默病的突触体小rna、突触损伤和认知能力下降