Characterizing novel Mixed Etiology Dementia models compromised for TDP-43 function

Project Summary / Abstract Alzheimer’s Disease (AD) and related dementias (ADRDs) are the leading causes of dementia and afflict millions of people every year, and projected cases are expected to rise exponentially due to the aging population. Clarification of disease mechanisms and target identification are critical unmet needs in the field. While the canonical amyloid-beta (Aß) and tau pathologies are implicated in AD cases, recent evidence revealed that non- canonical pathologies, including TDP-43 pathology, occur in the majority of cases. TDP-43 pathology is observed in up to 40% of all AD cases and about 50% of frontotemporal dementia (FTD) cases. Importantly, AD cases with TDP-43 pathology, compared to those without, exhibit steeper cognitive decline and more extensive brain atrophy. The underlying molecular mechanism of TDP-43 that drives neurodegeneration and cognitive impairments, however, remains elusive. Previous work in our lab, as well as other human studies, showed that loss of TDP-43 nuclear function, as opposed to its cytoplasmic aggregation, as a splicing repressor of cryptic exons underlies its pathology. To elucidate the molecular mechanisms by which loss of TDP-43 contributes to neuron loss, it is necessary to develop models of mixed etiology dementias (MEDs), which exhibit Aß and tau pathologies in combination with TDP-43 pathology, to mimic the human pathological context. Our lab previously showed that, in the presence of Aß plaque, expression of a human tau four-repeat fragment (Tau4R) can seed pathological conversion of endogenous tau, but additional risk factors are required to drive tauopathy. Due to the requirement of additional factors to promote tauopathy and our finding that loss of TDP-43 leads to worsened neurodegeneration, we hypothesize that loss of TDP-43 exacerbates tauopathy-driven neuron loss. Aim 1 will focus on characterizing an FTD and corticobasal degeneration (CBD)-like mouse model involving intraparenchymal injection of AAV.PhP.eB encoding Tau4R or Tau4R with an aggregation prone mutation in the hippocampus of mice conditionally lacking TDP-43 in forebrain neurons. I will use this same AAV-mediated approach in Aim 2 to characterize a model of AD with TDP-43 pathology, which involves Aß, tau, and TDP-43 pathologies. Both of these aims will involve evaluating the extent of tauopathy and neuron loss, examining microglia signatures, and correlating my findings in human tissue. Successful completion of the proposed research will help elucidate causal mechanisms of neurodegeneration and identify novel therapeutic targets for AD/ADRDs. Additionally, this project has immense training potential as I will gain new expertise across multiple techniques including biochemical tau protein extraction, Gallyus silver staining, single-cell RNA-Sequencing, bioinformatics and analysis of post-mortem human tissue. This research will be performed in a highly collaborative environment, where I will have numerous opportunities to receive quality mentorship and training, to develop my written and presentation skills, and to grow as a mentor to junior scientists.