Drivers of Vulnerability to Alzheimer’s Disease Neuropathological Changes
To identify molecular drivers of selective neuron vulnerability to tau and TDP-43, Aim 1 will employ neuron sub-type specific transcriptomics identifying gene expression differences among control and co-pathology C. elegans models. Top candidate genes and pathways will be assessed for impacts on tau and TDP-43 synergism using genetic loss-of-function or overexpression methods. To model co-morbid tau and TDP-43 in a mammalian brain, Aim 2 will use a new transgenic model of tau and TDP-43 co-expression to assess impacts of tau and TDP-43 on behavior, cognition, and neurodegeneration over time.
Our preliminary data are the first to demonstrate TDP-43 enhances tau neurotoxicity in specific neuronal populations. The experiments proposed here will dissect cellular, pathological, and functional changes underlying neuron vulnerability, allowing identification of new therapeutic targets and pathways. We will also determine cognitive, behavioral, and neurodegeneration consequences resulting from co-morbid tau and TDP-43 in the aging mammalian brain, which is an essential step to advance the field and rapidly progress our understanding of these disease processes. This work will develop and utilize new tools to understand mixed-pathology Alzheimer’s disease, significantly advancing our understanding of cellular changes in disease and creating resources for future scientific progress. In addition, these results will provide the groundwork for future therapeutic development targeting TDP-43 in Alzheimer’s disease to benefit everyone living with this disease.