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The interplay between Tau and ncRNAs – genomic and epigenomic clues to early AD pathogenesis

Tau 和 ncRNA 之间的相互作用 — 早期 AD 发病机制的基因组和表观基因组线索

基本信息

批准号：
10447273
负责人：
RADOSVETA KOLDAMOVA
金额：
$ 70.65万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2022-06-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447273
关键词：
Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease patient Amyloid beta-Protein Amyloid deposition Anatomy Animal Model Architecture Autopsy Binding Biochemical Biochemical Process Brain Brain region Cell Nucleus Cell physiology Cellular biology Chromatin Chromatin Structure Complex Cytoplasm Data Dementia Deposition Development Disease Early Diagnosis Epigenetic Process Event Family Gene Expression Genetic Genetic Transcription Genomics Genotype Goals Human Inferior Late Onset Alzheimer Disease Link Lobule MAPT gene Methylation Modification Molecular Molecular Genetics Mus Neurofibrillary Tangles Neurons Nuclear Nucleic Acid Regulatory Sequences Parietal Pathogenesis Pathologic Pathology Phosphorylation Physiological Plasma Play Proteins RNA RNA Binding RNA Processing RNA Splicing Research Research Personnel Role SNRPN Sampling Senile Plaques Site Small Nuclear RNA Small Nucleolar RNA Small RNA Transcriptional Regulation Translating Untranslated RNA age group amyloid precursor protein processing chromatin remodeling epigenomics extracellular extracellular vesicles functional disability genome-wide human subject hyperphosphorylated tau imprint mRNA Precursor mouse model neurofibrillary tangle formation neuron loss non-demented tau Proteins tau aggregation tool transcriptomics

项目摘要

Pathologically Late onset Alzheimer’s disease (AD) is characterized by extracellular amyloid plaques composed by aggregated Amyloid b and intracellular neurofibrillary tangles made of hyperphosphorylated TAU protein (encoded by MAPT gene). Recently, it has been shown that in human and mouse brain, tau co- immunoprecipitated with proteins and small RNAs that play a key role in in RNA modification and pre-mRNA splicing. It has been shown that cytosolic and nuclear tau aggregates are enriched for small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs) including SNORD115 and SNORD116 families of C/D box snoRNAs. Our preliminary data demonstrate a significant effect of Braak stage on expression level of snoRNAs and snRNAs in brain samples from AD patients as compared to controls. We also show that insoluble tau in AD but not control brains co-immunoprecipitated with selective snoRNAs of C/D box (SNORDs) but not H/A box (SNORA). We hypothesize that tau aggregates bind to snoRNAs and snRNAs and affect their traffic between the nucleus and cytoplasm. snoRNAs, snRNAs and hyperphosphorylated Tau in Tau-RNA complexes lose their physiological function in RNA processing and chromatin remodeling thus affecting chromatin accessibility and gene expression. This proposal's primary goal is to explore and demonstrate that selective regional vulnerability in AD brain and incremental hierarchical spreading of hyperphosphorylated Tau and deposition of NFT are associated and interconnected with changes in gene expression and chromatin architecture. We will achieve the goal by interrogating 3 distinct anatomical brain regions at different Braak stages from human subjects and animal models. Specific Aim 1: To conduct epigenomic and transcriptomic profiling across brain samples at different Braak stages and to detect tangle-specific changes in gene expression and chromatin structure. We will answer the question how NFT burden affects chromatin accessibility and gene expression. Specific Aim 2: To reveal a perturbed transcriptional control of SNORDs hosted on SNURF-SNRPN/UBE2A region on human Chr15 and to correlate their expression with the progression of AD tau pathology. We will identify snoRNAs and snRNAs bound to insoluble Tau aggregates and changes in methylation status within Chr15q11- q13 locus that affect transcriptional activity of SNURF-SNRPN domain. Specific Aim 3: Using AD mouse models to reveal the effect of hyperphosphorylated Tau and NFT on plasma, and brain-derived extracellular vesicles’ cargo. We will use PS19 mouse model and examine the effect of tau pathology in different age groups on the enrichment of snoRNA secreted in extracellular vesicles from brain, ISF, CSF and plasma.

病理上晚发性阿尔茨海默病（AD）以细胞外淀粉样斑块组成为特征