# Deteriming the Role of Caspase Cleaved Tau in Alzheimer’s Disease

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $72,082

## Abstract

Project Summary/Abstract
 Alzheimer’s disease (AD) is significant health threat that is the fastest growing top 10 cause of death in the
United States. AD currently costs Americans $280 billion dollars in direct health care costs annually. AD is
characterized by, among other things, fibrils of aggregated microtubule associated protein tau. Tau in these fibrils
is unique in several ways including truncation by caspases. The role of caspases and cleaved tau in AD has not
been clearly defined, and two non-mutually exclusive hypotheses have been proposed. The first hypothesis is
that caspases are being upregulated early in AD and cleave tau to a toxic species. A second possible explanation
is that caspases are overexpressed in response to tau upregulation and cleavage of tau occurs after AD
progression has been initiated.
 The overall goal of this proposal is understanding the role caspase cleaved tau plays in tau pathology. To
date, several truncated tau products have been observed in vivo, but most efforts to understand the role of these
products has revolved around genetic or chemical inhibition of caspases. Among all caspases, inhibition of
caspase-3 and capase-6 have shown to alleviate tau pathology and cell death in cell and animal models.
Knockout of caspase-3 is lethal in mice, but caspase-6 can be knocked out of mice without any adverse effects.
This begs the question, is caspases-6 a potential therapeutic target for the treatment of AD? For the answer to
this question to be yes, it must be shown why blocking caspase-6 alleviates tau pathology.
 Our central hypothesis is that caspase cleavage of tau results in a proteotoxic species that promotes
tauopathy and cell death in AD. To demonstrate this, we will first characterize where caspases can cleave tau in
a recombinant system. Next, we will characterize the stability, seeding propensity, cellular half-life, and toxicity
of these cleaved tau proteins. Finally, we will show that cells expressing uncleavable tau are resistant to toxicity
associated with caspase induction. These experiments will demonstrate that tau cleavage is necessary for
neuronal cell death induced by caspase induction. When combined with previous the observations that 1)
cleaved tau correlates with AD progression and 2) blockage of caspase activity alleviates tau pathology and cell
death, the proposed research will provide a strong case for caspases as therapeutic targets in AD.

## Key facts

- **NIH application ID:** 10386580
- **Project number:** 1F32AG072822-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Andrew J Ambrose
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $72,082
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386580

## Citation

> US National Institutes of Health, RePORTER application 10386580, Deteriming the Role of Caspase Cleaved Tau in Alzheimer’s Disease (1F32AG072822-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10386580. Licensed CC0.

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