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Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease

家族性阿尔茨海默病遗传忠实大鼠模型痴呆发病机制的研究

基本信息

批准号：
10557185
负责人：
LUCIANO D'ADAMIO
金额：
$ 78.7万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557185
关键词：
Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acids Amyloid beta-Protein Amyloid beta-Protein Precursor Brain Brain Pathology Brain imaging C-terminal Cannulas Cerebrospinal Fluid Cerebrum Code Cognition Cognitive Data Dementia Deposition Disease Early Onset Familial Alzheimer&apos s Disease Electrophysiology (science)Familial Dementias Functional Magnetic Resonance Imaging Genes Genetic Genetic Polymorphism Genetic Techniques Genomics Human Human Amyloid Precursor Protein Human Genetics Imaging Techniques Impaired cognition Inflammation Intelligence Knock-in Learning Link Mainstreaming Memory Microdialysis Modeling Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Organism Pathogenesis Pathogenicity Patients Peptides Pharmaceutical Preparations Physiological Processes Positron-Emission Tomography Procedures Process Protein Isoforms Protein Precursors Proteins Rattus Regulation Research Rodent Rodent Model Role Sampling Senile Plaques Signal Transduction Synaptic Transmission Tauopathies Testing Therapeutic Transgenic Mice Transgenic Model Transgenic Organisms Treatment Efficacy Variant Virulence Factors abeta accumulation alpha secretase amyloid precursor protein processing autosomal dominant mutation behavior test beta secretase beta-site APP cleaving enzyme 1 cognitive function design drug efficacy experimental study extracellular familial Alzheimer disease gamma secretase genetic approach genetic manipulation human disease implantation in vivo insight loss of function mutation model organism mouse model mutant neuroinflammation normal aging overexpression presenilin-1 presenilin-2 secretase tau Proteins tau-1 therapeutic evaluation therapeutic target

项目摘要

Project Summary/Abstract Alzheimer's Disease (AD) is the most common cause of ageing-dependent dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aβ peptides. These peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1 cleavage produces the C-terminal fragment, β-CTF, which is then processed into several Aβ isoforms by γ-secretase. Genetic data suggest that regulation of APP processing contributes to AD. In addition, a polymorphism of APP that reduces processing of APP by BACE1 protects from sporadic AD and from normal aging-dependent cognitive decline. Thus, the human genetic evidence indicates that APP and APP processing are important for normal cognitive functions. To gain insights into the pathogenic mechanisms of AD we introduced a familial APP mutation (the Swedish K670N/M671L mutation, AppS rats) and a familial PSEN1 mutation (L435F, Psen1LF rats) into the genomic App and Psen1 rat loci, respectively. Rat and human APP differ by 3 amino-acids in the Aβ region: given that aggregated forms of Aβ are considered by most the main pathogenic factor in AD, and given that human Aβ may have higher propensity than rodent Aβ to form yet-to-be-identified toxic forms of Aβ, together with the Swedish mutations we introduced mutations to “humanize” the rat Aβ sequence. As controls, we produced rats carrying only the humanized Aβ sequence (Apph rats). We choose a knock in (KI) approach rather than the more common transgenic overexpression approach because KI models make no preconceived assumption about pathogenic mechanisms, except the unbiased genetic one. In contrast, transgenic models, which produce high levels of Aβ and can readily deposit amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic Aβ have a central pathogenic role. We propose to dissect pathogenic mechanisms of neurodegeneration using these KI rat models of FAD. We will study the impact of App and Psen1 FAD mutations on APP processing, brain pathology, neuro-inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory. In addition, we will assess the role of distinct APP-derived metabolites in neurodegenerative processes triggered by mutant APP and PSEN1. These studies will test the mainstream hypotheses but also consider alterative pathogenic mechanisms, including the possibility that FAD pathogenesis may depend on the alteration of the normal function of APP and PSEN1 in the brain.

项目总结/文摘