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

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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.