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.

Grant Number: 5F31NS135935-03
NIH Institute/Center: NIH
Principal Investigator: Grace Burns