# Molecular Mechanisms of Synergistic TDP-43 and Tau Proteotoxicity in Alzheimer's Disease

> **NIH NIH K08** · UNIVERSITY OF WASHINGTON · 2020 · $141,834

## Abstract

Abstract
There are currently no disease modifying therapies for AD but many disease-relevant pathways remain under-
explored. This proposal seeks to understand the molecular mechanisms relating tau and TDP-43 pathology in
the context of late-onset Alzheimer’s disease (AD) by combining human neuropathology and gene expression
data with biological validation in a C. elegans model of proteotoxicity. Under the mentorship of Drs. Brain
Kraemer and Dirk Keene, this training and research plan will build on Dr. Latimer’s expertise in neuropathology
and prepare her for a career studying the proteotoxic pathways relevant to AD using C. elegans as a model
system. C. elegans represent an ideal system for investigating mechanisms of human disease given their ease
of transgenic modification, short life cycle, and recapitulation of the progressive neurodegeneration that is
characteristic of human proteinopathies. The five-year training plan includes research mentored by an
established team of experts and instruction in C. elegans research techniques, classification of TDP-43
proteinopathy, implementation of quantitative algorithms for immunohistochemistry in human tissue, and
analysis and interpretation of RNA-Seq data. This training will provide Dr. Latimer with the interdisciplinary
skills and knowledge necessary to achieve her long-term career goal to succeed as an independent physician
scientist with the expertise to advance the field of AD pathophysiology using C. elegans models of
proteotoxicity to link human pathology with the underlying mechanisms.
Data from human cohorts suggest a role for TDP-43 in the clinical expression of AD neuropathologic change.
This proposal will address the hypotheses that tau and TDP-43 synergize to drive neurodegeneration and that
targeting both toxic proteins may have stronger protective effects than targeting either alone. The project builds
on Dr. Latimer’s previous work with Drs. Kraemer and Liachko demonstrating the synergism between tau and
TDP-43 in a C. elegans model of combined proteotoxicity, and autopsy data in the Adult Changes in Thought
(ACT) study, a unique, longitudinal community-based cohort of older adults recruited from the Seattle area, in
which TDP-43 pathology is associated with dementia and increased pathologic tau. Dr. Latimer will test known
genetic modifiers of tau or TDP-43 neurotoxicity in the tau/TDP-43 C. elegans model (Aim 1) and determine
whether TDP-43 and tau pathology correlate in human brain tissue, leveraging data from the ACT autopsy
cohort (Aim 2). She will then use neuropathology data to select cases for RNA-Seq analysis in the ACT cohort
to identify novel modifiers of tau and TDP-43 proteotoxicity that can be biologically validated in the tau/TDP-43
C. elegans model (Aim 3). Completion of the aims will set the stage for future independent funding using
human genetic and neuropathologic data coupled with C. elegans models and lay the foundation for a new
generation of AD therapeutics t...

## Key facts

- **NIH application ID:** 9869125
- **Project number:** 1K08AG065426-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Caitlin Shannon Latimer
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $141,834
- **Award type:** 1
- **Project period:** 2020-01-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869125

## Citation

> US National Institutes of Health, RePORTER application 9869125, Molecular Mechanisms of Synergistic TDP-43 and Tau Proteotoxicity in Alzheimer's Disease (1K08AG065426-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869125. Licensed CC0.

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