Novel Mechanisms of tau and TDP-43 synergy in Alzheimer's disease

Alzheimer’s disease (AD), a severe progressive neurodegenerative disease of aging and the most common form of dementia, affects an estimated 30 million people worldwide. The presence of both amyloid plaques and neurofibrillary tangles pathologically define AD, however, TDP-43 pathology often occurs comorbidly with AD and correlates with more rapid cognitive decline and faster rates of hippocampal atrophy. We have previously shown that there is a synergistic relationship between tau and TDP-43 in a novel C. elegans model of combined tau and TDP-43 proteotoxicity, however the mechanisms that drive this interaction are unknown. In our C. elegans models we have performed bulk RNA sequencing to compare gene expression in transgenic animals expressing tau and TDP-43 alone and in combination. Preliminary results show that while tau pathology alone results in an upregulation of genes encoding lysosomal enzymes, these same genes show decreased expression in the combined tau and TDP-43 animals. We hypothesize that tau promotes a compensatory upregulation of the lysosomal autophagy pathway, as has been observed in human AD sequencing studies, but the combination of tau+TDP-43 impairs this response. In Aim 1 we will further interrogate this potential mechanistic pathway of tau and TDP-43 synergy by targeting specific genes involved in the lysosomal autophagy pathway in our C. elegans models of proteotoxicity. We will pair these functional assessments with a highly quantitative and spatially preserved interrogation of well-characterized human post- mortem samples to establish relevance to human disease and identify additional mechanisms of tau+TDP-43 synergy. One reason these pathways have remained elusive may be due to the heterogeneity of pTPD-43 pathology observed in AD. Distinct subtypes of pTDP-43 pathology have been described and our preliminary data suggest different relationships exist between tau and TDP-43 depending on the subtype present. In Aims 2 and 3 we will use NanoString technology to measure both protein and gene expression in key brain regions along the trajectory of pTDP-43 pathologic progression, taking into account the pTDP-43 morphologic subtype. Together, these studies will identify potential mechanisms that underly the observed synergistic proteotoxicty of tau and TDP-43, significantly advancing our understanding of the role of TDP-43 in the pathophysiology of AD and ultimately contributing to novel treatment and diagnostic strategies for AD with comorbid TDP-43 pathology in future work.