Genetic models of sporadic Alzheimers Disease in the marmoset

狨猴散发性阿尔茨海默病的遗传模型

• 批准号: 10281948
• 负责人: KUO-FEN LEE
• 金额: $ 141.04万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10281948
• 关键词: Affect; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amino Acids; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Apolipoprotein E; Apolipoproteins A; Arginine; Behavioral; Biochemical; Biological Models; Body Size; Brain; Brain Pathology; Callithrix; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Complex; Cysteine; Dementia; Dementia with Lewy Bodies; Disease; Environmental Risk Factor; Exhibits; Fishes; Genes; Genetic Models; Genomics; Genotype; Goals; Guide RNA; Homeostasis; Human; Incidence; Infection; Inflammation; Inflammatory Response; Link; Lipid Binding; Lipopolysaccharides; Longevity; Magnetic Resonance Imaging; Mediating; Meta-Analysis; Metabolism; Microglia; Modeling; Molecular; Molecular Disease; Mus; Mutation; Nerve Degeneration; Neurosciences Research; Parkinson' s Dementia; Pathology; Pathway interactions; Phenotype; Point Mutation; Positioning Attribute; Positron-Emission Tomography; Predictive Value; Primates; Protein Isoforms; Proteins; Relative Risks; Reproducibility; Research; Risk; Risk Factors; Role; Signal Transduction; Structure; Synapses; Tauopathies; Testing; Threonine; Transgenic Mice; Translating; Variant; Woman; age related; apolipoprotein E-3; cerebrovascular; cognitive testing; early onset; familial Alzheimer disease; fly; gain of function; genetic linkage analysis; genetic variant; genome wide association study; glucose metabolism; immune function; lipid transport; lipidomics; mouse model; mutant; neuroimaging; nonhuman primate; null mutation; overexpression; presenilin-1; presenilin-2; protective allele; protein TDP-43; reproductive; response; risk variant; sex; social; tau Proteins; therapeutic target; tool; transgenic model of alzheimer disease; translational neuroscience

Abstract The long-term goal of this project is to develop, characterize, and validate genetically modified marmoset models of sporadic Alzheimer's Disease (AD) that will serve as tools for investigating molecular and cellular disease mechanisms, and for identifying therapeutic targets. AD is the most common cause of dementia, with the majority of cases (~95%) appearing to be sporadic, which is caused by complex interactions between multiple gene variants and environmental factors. Numerous models of AD have been developed (e.g., mice); these models are primarily focused on familial forms of AD and have enabled significant progress toward understanding AD, but they fail to recapitulate the full spectrum of molecular, cellular, behavioral, and cognitive pathologies observed in AD and provide poor predictive value when trying to translate findings to human clinical trials. Several lines of evidence suggest that marmosets may effectively bridge the gap between mice and humans for both basic and translational neuroscience research. First, marmosets and humans have very similar brain structures, cognitive/social behavioral repertoires, metabolism, and immune functions. Second, compared to other primates, marmosets have short lifespan, small body size, and high reproductive power. Finally, gene editing tools are now available to generate various types of genetically modified marmosets. Apolipoprotein E (APOE) is the strongest risk factor for late-onset, sporadic AD and also increases the age- dependent risk of monogenic familial AD and incidence of AD in women. There are three APOE alleles in humans with the APOE*ε4 allele conferring increased risk and the APOE*ε2 allele conferring decreased risk relative to the common APOE*ε3 allele. APOE isoforms differentially modulate both amyloid-β (Aβ)-dependent and Aβ-independent pathways to affect brain homeostasis, including tau-mediated neurodegeneration, microglial inflammation, lipid transport, synaptic integrity, glucose metabolism and cerebrovascular function. These three APOE alleles differ with regard to cysteine (C) and arginine (R) amino acids at positions 112 and 158 (C112/C158 in APOE2; C112/R158 in APOE3; and R112/R158 in APOE4). Several lines of evidence demonstrate that R61 is critical for APOE4-mediated AD risk. Marmoset APOE (mAPOE) is encoded by a single allele and contains the equivalent of R112 and R158, but lacks the critical R61 equivalent (it contains T instead), suggesting that it behaves like human APOE3. To test this hypothesis, mAPOE T61R mutant protein was generated to test the effect on inflammatory responses induced by lipopolysaccharides in microglial cells. The mAPOE T61R variant resulted in a more robust response compared to wild type mAPOE. Similar results were found when human APOE4 was used (APOE4>APOE3). Taken together, these preliminary results indicate that mAPOE T61R is functionally equivalent to human APOE4. Further, several pairs of CRISPR gRNAs for generating an APOE null mutation have been identified. To investigate the role of APOE in sporadic AD in the marmoset, APOE null and T61R mutant marmosets will be generated and characterized.

摘要