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Mapping and Manipulating Cholingeric Basal Forebrain Activity in a Mouse Model of Alzheimer's Disease

阿尔茨海默病小鼠模型胆碱基前脑活动的绘制和操作

基本信息

批准号：
10285121
负责人：
Benjamin R Arenkiel
金额：
$ 40.13万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10285121
关键词：
Acetylcholine Acetylcholinesterase Inhibitors Activities of Daily Living Affect Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Animals Atlases Attention Award Behavioral Biological Biological Assay Body Weight Brain Cell physiology Cholinesterase Inhibitors Cognition Cognitive deficits Control Groups Data Decision Making Dementia Disease Disease Progression Functional Imaging Functional Magnetic Resonance Imaging Gene Expression Gene Expression Profiling Gene Mutation Human Image Impaired cognition Intervention Knock-in Mouse Knowledge Maps Measures Memory Molecular Molecular Analysis Molecular Profiling Mus Mutation NMDA receptor antagonist Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Parents Pathogenesis Pathologic Pathology Performance Pharmacologic Substance Pharmacotherapy Physical Exercise Physiological Psyche structure Reagent Research Role Senile Plaques Signal Transduction Symptoms Therapeutic Tissues United States Weight maintenance regimen basal forebrain basal forebrain cholinergic neurons base brain cell brain tissue calcium indicator cell type cholinergic cognitive function design disease phenotype environmental enrichment for laboratory animals experimental study extracellular genetic manipulation human disease hyperphosphorylated tau improved in vivo in vivo imaging insight mouse model neural circuit neurotransmission optogenetics parent grant recombinant virus response symptomatology therapeutic target tool transcriptome two-photon

项目摘要

PROJECT SUMMARY Alzheimer’s Disease (AD) is the most common form of dementia, affecting roughly 5.8 million people in the United States. Primary pharmaceutical interventions for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonists, are capable of temporarily improving cognitive function, but no current treatments exist to halt or reverse AD progression. Several histopathological hallmarks manifest in AD patients, including formation of extracellular Aβ plaques, neurofibrillary tangles, and accelerated degeneration of basal forebrain cholinergic neurons (BFCNs). This marked BFCN degeneration is believed to be a major underlying cause of the cognitive deficits observed in human AD patients throughout disease progression. This supplemental application proposes to utilize tools and information garnered through current research being conducted the parent award “Genetically dissecting cholinergic signaling in body weight control” (R01DK109934), where we have selectively targeted basal forebrain cholinergic neurons for genetic manipulations and biological analysis, to elucidate either their involvement in AD. We will specifically investigate if BFCNs contribute to AD progression with their loss, or provide potential neuroprotective avenues with activation.

项目摘要阿尔茨海默氏病（AD）是最常见的痴呆症，在美国约有580万人受到影响。美国的AD的主要药物干预，如乙酰胆碱酯酶抑制剂和NMDA 受体拮抗剂能够暂时改善认知功能，但目前还没有治疗方法，停止或逆转AD进展。AD患者的几个组织病理学特征，包括形成细胞外Aβ斑块、神经元缠结和基底前脑胆碱能神经元的加速变性神经元（BFCN）。这种显著的BFCN变性被认为是认知障碍的主要潜在原因。在整个疾病进展过程中在人类AD患者中观察到的缺陷。本补充申请提出利用目前正在进行的研究所获得的工具和信息，解剖体重控制中的胆碱能信号传导”（R01DK109934），我们选择性地靶向基底前脑胆碱能神经元进行遗传操作和生物学分析，以阐明它们的参与AD。我们将专门研究BFCN是否会随着其丢失而导致AD进展，或者通过激活提供潜在的神经保护途径。