Project 3 (BNI)-Cholinergic alteration in mild cognitive impairment

项目3（BNI）-轻度认知障碍中的胆碱能改变

• 批准号: 10132952
• 负责人: ELLIOTT Jay MUFSON
• 金额: $ 79.99万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10132952
• 关键词: Affect; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Amyloid; Animals; Anterior; Anterolateral; Antibodies; Apolipoprotein E; Autopsy; Basal Nucleus of Meynert; Basic Science; Cells; Cholinesterase Inhibitors; Clinical; Cognition; Cognitive; Cohort Studies; Complex; Data; Defect; Dementia; Development; Disease; Disease Progression; Dorsal; Drug Design; Drug Targeting; Elderly; Episodic memory; Event; Evolution; Executive Dysfunction; Exons; Functional disorder; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Heterogeneous-Nuclear Ribonucleoproteins; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Individual; Intervention; Laboratories; Libraries; Link; Medial; Memory; Messenger RNA; Metabolic; Molecular; Neocortex; Nerve Degeneration; Neurobiology; Neurofibrillary Tangles; Neurons; Nuclear; Onset of illness; Optics; Participant; Pathogenicity; Pathology; Pattern; Pharmaceutical Preparations; Phosphotransferases; Plant Roots; Play; Population; Post-Translational Protein Processing; Protein Isoforms; Proteins; RNA Splicing; RNA Stability; RNA metabolism; Reporting; Ribosomal RNA; Risk; Role; SRSF2 gene; Series; Sirtuins; Site; Spliceosomes; Study Subject; Subgroup; Symptoms; System; Technology; Temporal Lobe; Testing; Tissue Sample; Tissues; Translating; U1 Small Nuclear Ribonucleoprotein; Untranslated RNA; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; cingulate cortex; connectome; density; early detection biomarkers; executive function; familial Alzheimer disease; frontal lobe; immunocytochemistry; improved; in vivo; innovation; invention; mild cognitive impairment; morphometry; nervous system disorder; neurofibrillary tangle formation; neuroimaging; neurotransmission; novel; novel marker; pre-clinical; prodromal Alzheimer' s disease; protein expression; religious order study; spatiotemporal; tau Proteins; tau expression; tau phosphorylation; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Despite the fact that by the year 2050 older people at risk for cognitive decline and Alzheimer’s disease (AD) are predicted to reach 13 million, treatment approaches are woefully lacking. Although cholinergic dysfunction is a mainstay of AD, and cholinesterase inhibitors remain the drugs of choice for the management of mild to moderate AD, it does not prevent disease onset or modify its progression. Our goal is to elucidate the earliest molecular and cellular events underlying the selective neuronal vulnerability of the cholinergic basal forebrain (CBF) memory and executive function interactome in order to provide new and improved CBF interventions, to be used in combination with drugs that target other AD hallmarks, (e.g., tau and amyloid) during the preclinical stage of the disease. In AD, the magnitude of CBF neuron and volume loss and neurofibrillary tangle (NFT) formation displays a rostrocaudal pattern with greatest neurodegeneration in the posterior followed by the intermediate and then the anterior subfield, the least affected cholinergic (Ch4) subgroup. The Ch4 subfields were recently recognized as a as a critical subcortical regulatory node of the default mode network (DMN), which displays circuit-driven AD pathology associated with episodic memory and executive function deficits early in AD. CBF degeneration is not only manifested by specific post-translational tau modifications, but by a confluence of intracellular events that occur prior to the onset of clinical symptoms. We recently provided novel evidence that presplicing U1 small nuclear ribonucleoproteins (snRNPs) aggregate and are associated with NFTs in sporadic and familial AD, but not other neurologic diseases. We now report that defects in presplicing proteins are involved in CBF neuronal degeneration during the earliest preclinical stages of AD. Project 3 will translate information derived from a uniquely human condition, preclinical AD. Notwithstanding the conceptually and technically inventive approaches employed (i.e., oligomeric tau and presplicing antibodies, single population microarray and RNA sequencing approaches), studying the role(s) that presplicing plays in NFT evolution within vulnerable CBF neurons using clinically and neuropathological well-characterized same from preclinical, MCI and AD cases from the Rush Religious Orders Study (RROS) is highly innovative. Project 3 is posited to lay the groundwork for a wide range of potential interventions via transcriptionally aided drug design and suggest novel biomarkers for early AD diagnosis.

项目总结/摘要 尽管到2050年，老年人面临认知能力下降和阿尔茨海默病（AD）的风险， 预计将达到1300万，但治疗方法却严重缺乏。虽然胆碱能功能障碍是 是AD的支柱，胆碱酯酶抑制剂仍然是治疗轻度至 中度AD，它不能预防疾病发作或改变其进展。我们的目标是阐明 胆碱能基底前脑选择性神经元易损性的分子和细胞事件 (CBF)记忆和执行功能相互作用组，以提供新的和改进的CBF干预， 与靶向其他AD标志的药物联合使用，（例如，tau蛋白和淀粉样蛋白） 疾病的阶段。在AD中，CBF神经元的数量、体积损失和神经原纤维缠结（NFT） 形成显示了一个喙尾模式，最大的神经变性在后面，其次是 中间，然后是前场，受影响最小的胆碱能（Ch 4）亚组。Ch 4子字段 最近被认为是默认模式网络（DMN）的关键皮层下调节节点， 其显示与情景记忆和执行功能缺陷相关的电路驱动的AD病理学 早在AD。CBF变性不仅表现为特异性的翻译后tau蛋白修饰，而且表现为特异性的翻译后tau蛋白修饰。 在临床症状发作之前发生的细胞内事件的汇合。我们最近提供了一个新的 有证据表明，预剪接U1小核核糖核蛋白（snRNP）聚集，并与 NFT用于散发性和家族性AD，但不用于其他神经系统疾病。我们现在报告预拼接中的缺陷 这些蛋白质在AD的最早临床前阶段参与CBF神经元变性。项目3将 翻译来自独特的人类疾病，临床前AD的信息。尽管概念上 以及所采用的技术上的创造性方法（即，寡聚tau和预剪接抗体，单 群体微阵列和RNA测序方法），研究预剪接在NFT中的作用 脆弱的CBF神经元内的演变，使用临床和神经病理学良好表征的相同， Rush Religious Orders Study（RROS）的临床前、MCI和AD病例是高度创新的。项目3是 为通过转录辅助药物设计进行广泛的潜在干预奠定基础 并为AD的早期诊断提供了新的生物标志物。