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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

基本信息

批准号：
10427159
负责人：
ELLIOTT Jay MUFSON
金额：
$ 80.08万
依托单位：
ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10427159
关键词：
Affect Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos 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&apos s disease protein expression religious order study spatiotemporal tau Proteins tau expression tau phosphorylation transcriptome sequencing

项目摘要

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/文摘