# Generation and characterization of a mouse model exhibiting beta-amyloidosis and tauopathy with nuclear depletion of TDP-43

> **NIH NIH R33** · JOHNS HOPKINS UNIVERSITY · 2022 · $667,007

## Abstract

Alzheimer's Disease-Related Dementias (ADRD) is a group of progressive neurodegenerative
disorders with mid to late life onset such as mixed etiology dementias (MED) including Alzheimer's
disease (AD) with TDP-43 pathology. To clarify disease mechanisms and identify therapeutic targets,
a new mouse models that replicate combinations of co-occurring pathological features of human
dementia will be critical. It is well recognized that AD cases with TDP-43 pathology, as compared to
those without, showed a greater decline in cognitive deficits. However, the molecular mechanisms
underlying such contribution of TDP-43 remains elusive. We showed that TDP-43 pathology is due to
loss of TDP-43's nuclear function, particularly its ability to repress cryptic exon splicing, that precedes
formation of TDP-43 cytoplasmic aggregates. That splicing repression is a major role of TDP-43 in
forebrain neurons led us to hypothesize that loss of TDP-43 repression exacerbates neurodegeneration
and cognitive deficits. To address this question, we will take advantage of 1) our model lacking TDP-
43 in forebrain neurons which exhibits age-dependent neuron loss, cognitive deficits and defects in
prelimbic cortical circuits; and 2) our tau model which show, in presence of amyloid plaques, tauopathy-
dependent neuron loss, to develop a novel MED model that would exhibit beta-amyloidosis and
tauopathy along with compromised TDP-43 repression in forebrain neurons, pathological features that
mimic AD with loss of TDP-43 repression. By employing a comprehensive set of molecular,
pathological, neuronal circuit and behavioural/cognitive approaches, we will rigorously characterize the
MED mice across their lifespan, providing a highly innovative and instructive model to clarify disease
mechanism and identify therapeutic targets.

## Key facts

- **NIH application ID:** 10618759
- **Project number:** 4R33NS115161-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** PHILIP C WONG
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $667,007
- **Award type:** 4N
- **Project period:** 2019-09-17 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10618759

## Citation

> US National Institutes of Health, RePORTER application 10618759, Generation and characterization of a mouse model exhibiting beta-amyloidosis and tauopathy with nuclear depletion of TDP-43 (4R33NS115161-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10618759. Licensed CC0.

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