# Mechanisms of TDP-43 neurotoxicity in Alzheimer's disease

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2024 · —

## Abstract

Alzheimer's disease, a severe progressive neurodegenerative disease of aging and the most common form
of dementia, affects an estimated 30 million people worldwide. Pathologically, Alzheimer's disease is
defined by the presence of both amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary
tangles containing the protein tau in disease affected brain regions. However, more than half of Alzheimer's
disease patients also exhibit TDP-43 aggregates as an additional co-pathology. The presence of TDP-43
pathology in Alzheimer's disease correlates with hippocampal sclerosis, worse brain atrophy, more severe
cognitive impairment, and more rapid cognitive decline. Given the recent recognition of TDP-43 as a
frequent co-pathology in Alzheimer's disease, understanding its contribution to neurodegenerative disease
processes and potential synergies with other pathological disease-promoting proteins is a critical need in
the field. Recent work using C. elegans found that co-expressed tau and TDP-43 leads to increased
neurotoxicity and pathological protein accumulation. Building on this foundation, the proposed Aims will
develop and utilize new models of co-expressed tau and TDP-43 in order to understand the biology
underlying their synergistic toxicity. Aim 1 will define tau isoform and TDP-43 protein domain requirements
for enhanced neurotoxicity using precision gene editing, combined with sensitive behavioral and
neuroimaging assays in C. elegans. Aim 2 will use a new mouse model of tau and TDP-43 co-expression to
map neuronal vulnerabilities, pathological protein accumulation, and neurodegeneration through aging in
the mammalian brain. We will also determine cell specific responses to co-morbid tau and TDP-43 using
spatial transcriptomics. This work will characterize mechanisms underlying tau and TDP-43 neurotoxicity in
Alzheimer's disease and identify new therapeutic targets and strategies. Completion of this project will
significantly advance understanding of Alzheimer's disease with comorbid TDP-43, and provide the
groundwork for future therapeutic development targeting TDP-43 in Alzheimer's disease.

## Key facts

- **NIH application ID:** 10721823
- **Project number:** 5I01BX005762-02
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** Nicole Faron Liachko
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721823

## Citation

> US National Institutes of Health, RePORTER application 10721823, Mechanisms of TDP-43 neurotoxicity in Alzheimer's disease (5I01BX005762-02). Retrieved via MORVS 2026-10-27 from https://api.morvs.ai/grant/nih/10721823. Licensed CC0.

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