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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.

迟发性阿尔茨海默病(AD)的病理特征是细胞外淀粉样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原纤维缠结 (由MAPT基因编码)。最近，研究表明，在人和小鼠的大脑中，tau-co- 与在RNA修饰和前-mRNA中起关键作用的蛋白质和小RNA进行免疫沉淀拼接。已有研究表明，胞质和核内的tau聚集体对小的核rna具有浓缩性。小核仁RNA(SnoRNAs)，包括C/D盒的SNORD115和SNORD116家族 SnoRNA。我们的初步数据显示Braak分期对snoRNAs的表达水平有显著影响与对照组相比，AD患者大脑样本中的SnRNAs。我们还证明了在公元一年中，不可溶的tau 但不控制与选择性C/D盒snoRNAs(SNORD)共沉淀的大脑，而不是H/A盒 (SNORA)。我们假设tau聚集体与snoRNAs和snRNAs结合，并影响它们在细胞核之间的交通和细胞质。Tau-RNA复合体中的SnoRNAs、SnRNAs和过度磷酸化的Tau失去其生理功能在RNA加工和染色质重塑中的作用，从而影响染色质的可及性和基因表达。该提案的主要目标是探索和证明AD大脑和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的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从人类受试者和动物模型中询问不同Braak阶段的3个不同的大脑解剖区域。具体目标1：在不同Braak的大脑样本之间进行表观基因组和转录图谱分析并检测基因表达和染色质结构的缠结特异性变化。我们将回答问一问NFT负担如何影响染色质的可及性和基因表达。特定目标2：揭示SNURF-Snrpn/UBE2A上SNORD的转录调控并研究其表达与AD tau病理进展的关系。我们将确定与不溶性Tau聚集体结合的SnoRNAs和SnRNAs以及Chr15q11内甲基化状态的变化- 影响SNURF-Snrpn结构域转录活性的Q13基因座。具体目标3：利用AD小鼠模型揭示过度磷酸化的Tau和NFT对血浆的影响，和脑源性细胞外小泡的货物。我们将使用PS19小鼠模型并检测tau的作用。不同年龄组脑细胞外小泡分泌snoRNA的病理变化脑脊液和血浆。