Evaluating the Role of the TDP-43 Protein in Alzheimer's Disease Pathogenesis

This project aims to elucidate the role of TDP-43 dysfunction in the pathogenesis of Alzheimer’s.

TDP-43 proteins abnormally accumulate in the brain of up to 70% of people with Alzheimer’s disease and are characterized by worse memory and greater brain atrophy compared to those with Alzheimer’s lacking TDP-43 pathology. This proposal aims to characterize the role of TDP-43 dysfunction in the pathogenesis of Alzheimer’s by evaluating: 1) whether TDP-43 dysfunction exacerbates behavior and pathological Alzheimer’s phenotypes, as well as induces neuronal loss in an Alzheimer’s mouse model, and 2) the relationships between Alzheimer’s pathologies and TDP-43 dysfunction in Alzheimer’s human brains.

These studies are expected to also highlight the importance of TDP-43 pathology in therapeutic target and biomarker design and in participant evaluations during clinical trials.

Understanding the role of TDP-43 dysfunction in AD pathogenesis has been hindered by the lack of mouse models that recapitulate key aspects of the human disease. Our novel mouse models are expected to aid fill this gap, ultimately elucidating the importance of TDP-43 in neurodegenerative processes in AD. We also have access to many AD brain tissues from patients to better study the relevance of our findings to humans. These studies are expected to increase understanding on AD disease mechanisms, involvement of TDP-43 dysfunction in neurodegeneration, and clinical heterogeneity.

These studies are expected to increase understanding on AD disease mechanisms, involvement of TDP-43 dysfunction in neurodegeneration, and clinical heterogeneity. Our studies are expected to also highlight the importance that this pathology may have in therapeutic target and biomarker design, as well as in patient stratification for clinical trials.