TDP-43 in Alzheimer's disease

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Alzheimer’s disease, a severe progressive neurodegenerative disease of aging and the most common form of dementia, affects an estimated 30 million people worldwide. Pathologically, Alzheimer’s disease is defined by the presence of both amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau in disease affected brain regions. However, 30-57% of Alzheimer’s disease patients also exhibit TDP-43 aggregates as an additional co-pathology. The presence of TDP-43 pathology in Alzheimer’s disease correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. Given the recent recognition of TDP-43 as a frequent co- pathology in Alzheimer’s disease, understanding its contribution to neurodegenerative disease processes and potential synergies with other pathological disease-promoting proteins is a critical need in the field. Recent work using C. elegans found that co-expressed tau and TDP-43 leads to increased neurotoxicity and pathological protein accumulation. Building on this foundation, the proposed Aims will develop and utilize new tractable models of co-expressed tau and TDP-43 in order to understand the biology underlying their toxicity. Aim 1 will define consequences of low or regulatable levels of co-expressed tau and TDP-43 using behavioral and neuroimaging assays, and test relationships between tau and TDP-43. Aims 2 and 3 will employ RNA sequencing to reveal gene expression underlying comorbid tau and TDP-43 through aging in simple models, and in human post-mortem brain tissue from patients with Alzheimer’s disease with TDP-43 pathology. Candidates nominated from transcriptomic approaches will be tested for functional roles in tau and TDP-43 synergistic proteinopathy using genetic and transgenic approaches. This work will characterize mechanisms underlying tau and TDP-43 neurotoxicity in Alzheimer’s disease and identify new therapeutic targets and strategies. Completion of this project will significantly advance understanding Alzheimer’s disease with comorbid TDP-43, and provide the groundwork for future therapeutic development targeting TDP-43 in Alzheimer’s disease.