Brain aging and Alzheimer's related dementias: convergence onto retrotransposons and endogenous retroviruses

项目摘要 该提案调查了老龄化影响以下风险的机制： 阿尔茨海默氏症和相关痴呆症（ADRD）。这一提议的核心假设是 衰老和神经退行性蛋白质病理学协同作用， 逆转录转座子和内源性逆转录病毒。拟议中的工作将检验这一想法 年龄影响ADRD发病的风险，逆转录转座子影响ADRD发病率。 下降这些移动的元素导致DNA损伤，导致非细胞自主 神经胶质对附近神经元的毒性。拟议的工作将系统地改变 在ADRD模型的背景下，老化/寿命，并测试影响， 逆转录转座子和内源性逆转录病毒的毒性。直接读出 动物的健康和寿命将与反转录转座子表达相关， 复制和功能操作也将被使用。

PROJECT ABSTRACT This proposal investigates the mechanisms by which aging impacts the risks of Alzheimer’s and related dementias (ADRD). The central hypothesis of this proposal is that age and neurodegenerative protein pathology synergize to activate retrotransposons and endogenous retroviruses. The proposed work will test the idea that age impacts the risk of ADRD onset, and that retrotransposons impact the rate of decline. These mobile elements cause DNA damage, leading to non-cell autonomous toxicity of glia to nearby neurons. The proposed work will systematically vary aging/longevity in the context of models of ADRD, and test the impacts as measured by the toxicity of retrotransposons and endogenous retroviruses. Direct readouts of the health and lifespan of the animals will be correlated with retrotransposon expression and replication, and functional manipulations will be used as well.