Reduced allelic dosage of CLP1 attenuates cognitive dysfunction and pathological burden in transgenic mouse models of Alzheimer’s disease

减少 CLP1 等位基因剂量可减轻阿尔茨海默病转基因小鼠模型的认知功能障碍和病理负担

• 批准号: 10572250
• 负责人: Ashleigh E Schaffer
• 金额: $ 15.52万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10572250
• 关键词: AD transgenic mice; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Attenuated; Basic Science; Behavioral; Biochemical; Bioinformatics; Biological Markers; Brain; Brain Pathology; Caregivers; Cause of Death; Childhood; Clinical; Collaborations; Complex; Cytoplasm; Data; Defect; Dementia; Deposition; Disease; Disease Progression; Elderly; Environmental Risk Factor; Foundations; Functional disorder; Future; Genes; Genetic; Goals; Heterozygote; Histologic; Histology; Impaired cognition; Mediator; Messenger RNA; Molecular; Motor Neuron Disease; Mus; Mutant Strains Mice; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Nuclear RNA; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Persons; Phenotype; Phosphorylation; Phosphotransferases; Prior Therapy; Proteins; Psyche structure; RNA; RNA Processing; RNA-Binding Proteins; Research; Research Design; Sampling; Senile Plaques; Series; Testing; Tissue Sample; Transgenic Mice; Up-Regulation; Variant; Western Blotting; Work; behavior test; brain tissue; causal variant; cognitive ability; cognitive function; comparison control; design; disorder risk; dosage; effective therapy; experience; genetic risk factor; improved; in vivo; mouse model; novel; overexpression; preservation; protein TDP-43; protein expression; therapeutic development; therapeutic target; transcriptomics

Project Summary/Abstract Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly caused by complex interactions of genetic and environmental risk factors. An estimated 130 million people will develop AD by 2050, constituting an urgent clinical need for effective treatments and therapies to be developed. Prior therapies have focused on resolving pathological hallmarks, such as senile plaques (Ab) and neurofibrillary tangles (tau), but have failed to improve cognitive function in patients. The RNA kinase, CLP1, was recently found to be a genetic mediator AD. Additionally, high mRNA levels of CLP1 correlated with poor cognitive function in patients. Our preliminary histological analysis of brain samples from dementia patients and a mouse model of AD, with controls, found a shared, aberrant expression pattern of CLP1 protein with disease. Together, these findings lead us to hypothesize that CLP1 overexpression may contribute to AD pathogenesis and cognitive decline in AD. To test this idea, we will intercross mouse models of AD with Clp1 heterozygous mutant mice and assess disease pathology and cognitive decline during AD progression for amelioration.

项目摘要/摘要 阿尔茨海默病(AD)是老年人中最常见的痴呆形式，由复杂的相互作用引起 遗传和环境风险因素。据估计，到2050年，将有1.3亿人患上阿尔茨海默病， 临床迫切需要开发有效的治疗方法和治疗方法。以前的治疗方法主要集中在 解决病理特征，如老年斑(Ab)和神经原纤维缠结(Tau)，但失败 改善患者的认知功能。最近发现的RNA激酶CLP1是一种遗传调节因子AD。 此外，CLP1的高水平与患者的认知功能低下相关。我们的预赛 对痴呆症患者和AD小鼠模型的大脑样本进行的组织学分析发现， CLP1蛋白在疾病中的共享、异常表达模式。总而言之，这些发现引导我们 推测CLP1的过度表达可能参与了AD的发病机制和认知功能的下降。 为了测试这一想法，我们将使阿尔茨海默病小鼠模型与CLP1杂合突变小鼠杂交，并评估疾病 阿尔茨海默病进展过程中的病理和认知功能下降以寻求改善。