Mechanisms of TDP-43 neurotoxicity 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, more than half 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 models of co-expressed tau and TDP-43 in order to understand the biology underlying their synergistic toxicity. Aim 1 will define tau isoform and TDP-43 protein domain requirements for enhanced neurotoxicity using precision gene editing, combined with sensitive behavioral and neuroimaging assays in C. elegans. Aim 2 will use a new mouse model of tau and TDP-43 co-expression to map neuronal vulnerabilities, pathological protein accumulation, and neurodegeneration through aging in the mammalian brain. We will also determine cell specific responses to co-morbid tau and TDP-43 using spatial transcriptomics. 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 of Alzheimer's disease with comorbid TDP-43, and provide the groundwork for future therapeutic development targeting TDP-43 in Alzheimer's disease.