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.

项目概要/摘要 阿尔茨海默病 (AD) 是老年人中最常见的痴呆症，由复杂的相互作用引起 遗传和环境风险因素。预计到 2050 年将有 1.3 亿人患 AD， 临床迫切需要开发有效的治疗方法。先前的治疗主要集中在 解决病理标志，如老年斑 (Ab) 和神经原纤维缠结 (tau)，但未能 改善患者的认知功能。最近发现 RNA 激酶 CLP1 是 AD 的遗传介质。 此外，CLP1 mRNA 水平高与患者认知功能差相关。我们的初步 对痴呆症患者和 AD 小鼠模型以及对照组的大脑样本进行组织学分析，发现 CLP1 蛋白与疾病共有的异常表达模式。总之，这些发现引导我们 假设 CLP1 过度表达可能导致 AD 发病机制和 AD 认知能力下降。 为了验证这个想法，我们将 AD 小鼠模型与 Clp1 杂合突变小鼠进行交叉并评估疾病 AD 进展期间病理学和认知能力下降的改善。