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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.

晚发性阿尔茨海默病（AD）的病理特征是细胞外淀粉样蛋白斑块，通过聚集的淀粉样蛋白B和由过度磷酸化的TAU蛋白组成的细胞内神经元缠结（由MAPT基因编码）。最近，研究表明，在人类和小鼠的大脑中，tau蛋白与与在RNA修饰和前mRNA中起关键作用的蛋白质和小RNA免疫沉淀拼接已经表明，细胞溶质和细胞核tau聚集体富含小的核RNA，包括C/D盒的SNORD 115和SNORD 116家族的小核仁RNA（snoRNA）。 snoRNAs。我们的初步数据表明，Braak阶段对snoRNA的表达水平有显着影响和snRNA在来自AD患者的脑样品中与对照相比。我们还表明，AD中不溶性tau蛋白而不是与C/D盒（SNORD）而不是H/A盒的选择性snoRNA免疫共沉淀的对照脑（SNORA）。我们假设tau聚集体与snoRNA和snRNAs结合并影响它们在细胞核之间的运输和细胞质。snoRNA、snRNA和Tau-RNA复合物中的过度磷酸化Tau失去了它们的生理活性。在RNA加工和染色质重塑中起作用，从而影响染色质可及性和基因表达。该提案的主要目标是探索和证明AD大脑中的选择性区域脆弱性，过度磷酸化Tau的递增分级扩散和NFT沉积相关，与基因表达和染色质结构的变化相互关联。我们将通过以下方式实现目标：询问人类受试者和动物模型在不同Braak阶段的3个不同解剖大脑区域。具体目标1：在不同Braak水平的脑样本中进行表观基因组和转录组分析阶段，并检测基因表达和染色质结构的缠结特异性变化。我们将回答 NFT负荷如何影响染色质可及性和基因表达。具体目的2：揭示SNORD在SNURF-SNRPN/UBE 2A上的受扰转录控制区域，并将它们的表达与AD tau病理学的进展相关联。我们将确定 snoRNA和snRNA与不溶性Tau聚集体结合以及Chr 15 q11内甲基化状态的变化 q13位点影响SNURF-SNRPN结构域转录活性。具体目的3：使用AD小鼠模型来揭示过度磷酸化的Tau和NFT对血浆的影响，和脑源性细胞外囊泡的货物。我们将使用PS19小鼠模型并检查tau蛋白的作用。不同年龄组的病理学对脑细胞外囊泡分泌的snoRNA富集的影响，ISF，脑脊液和血浆。