# Enhancing proteasomal activity and tau clearance via USP14 reduction in Alzheimer's Disease mouse models

> **NIH NIH F31** · WASHINGTON UNIVERSITY · 2024 · $34,623

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD), a progressive neurodegenerative disease causing memory loss, is the primary cause
of dementia. Recent FDA approval of an amyloid beta-targeting medicine represents a significant advance in AD
treatment, yet effective therapies for tau pathology remain crucial. Tau accumulation and neurofibrillary tangles
are central to AD pathology and strongly correlate with cognitive decline and neuronal loss1. Therefore, strategies
that seek to interrupt tau deposition and propagation may be effective treatments. Regions associated with tau
accumulation2 in postmortem AD brains show reduced proteasome activity, suggesting impaired protein
degradation may contribute to tau pathology. Thus, increasing proteasome activity to degrade tau may be an
efficient therapy to reduce tau burden and neurodegeneration. The ubiquitin-proteasome system is negatively
regulated, in part, by enzymes that remove the ubiquitin side chains from proteins targeted to the proteasome.
Among these enzymes, the ubiquitin-specific protease 14 (Usp14) selectively acts on substrates, including tau,
to reduce or prevent their degradation. This proposal tests an antisense oligonucleotide (ASO)-mediated
approach to reduce Usp14 in the central nervous system, increasing proteasomal degradation of tau. ASOs are
short, single-stranded DNA that bind to target mRNA to decrease or modify the protein expression through the
recruitment of RNAse H. In recent years, ASOs have become valuable tools for understanding and treating
neurodegenerative diseases, and improved chemistries and delivery methods have made ASOs safe and
effective in multiple clinical trials3,4. Preliminary data show that Usp14-lowering ASO treatment activates the
proteasome system and decreases total tau in neurons and tau transgenic mice. Using this effective tool, this
proposal will assess the effects of proteasome activation on tau pathology and tau seeding in a mouse model of
tau-mediated neurodegeneration. Aim 1 will test the effects of proteasomal activation via Usp14 lowering on tau
pathology and gliosis in mutant P301S tau transgenic mice (PS19). I will intraventricularly administer Usp14-
lowering ASOs to PS19 mice at early (3 months), mid (6 months), and late (9 months) stage pathology to evaluate
neurofibrillary tangle formation, neuronal loss, gliosis, and potential off-target effects using
immunohistochemistry, mass spectrometry, and ELISA assays. Aim 2 will investigate proteasomal activation's
role in preventing tau seeding in vitro and its propagation in vivo. In vitro, primary neurons will be treated with
GFP-labeled bioactive tau seeds, followed by Usp14-lowering ASO to activate the proteasome system. I will
assess amount of GFP-labeled tau seeds and total aggregated tau to evaluate seeding efficiency. In vivo,
wildtype mice will be injected with tau seeds and subsequently treated with Usp14-lowering ASO. The extent of
tau propagation will be quantified by assessing the sprea...

## Key facts

- **NIH application ID:** 10995921
- **Project number:** 1F31AG084257-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Miwei Hu
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,623
- **Award type:** 1
- **Project period:** 2024-09-16 → 2027-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995921

## Citation

> US National Institutes of Health, RePORTER application 10995921, Enhancing proteasomal activity and tau clearance via USP14 reduction in Alzheimer's Disease mouse models (1F31AG084257-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10995921. Licensed CC0.

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