# Tau protein proteolysis signaling in Alzheimer's disease

> **NIH NIH R21** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2023 · $431,750

## Abstract

Project Summary
Pathologic Tau protein self-assembly templating and stereotypical regional spreading along neuronal networks
correlates with loss of neurons and is central to clinical progression and staging in Alzheimer’s disease (AD). In
diseased brain, Tau molecules begin to form filamentous aggregates with a rigid β-sheet rich core. Although
some Tau protein fragments can spontaneously aggregate, recombinant full-length Tau produced in vitro or
when expressed in mammalian cells does not aggregate spontaneously even at supersaturation. To initiate
Tau protein to form aggregates, some unknown energy barrier must be overcome. Research shows that
inducing Tau monomer to form a nucleus leading to filamentous elongation can be a heterogenous association
such as with a membrane, small molecules, or peptides stabilizing the misfolded species for subsequent
elongation steps. Proteolysis is a process of protein degradation which also controls multiple cellular functions.
Tau is a natively unfolded protein sensitive to protease digestion and the longest human brain isoform contains
more than forty cleavage sites which leads to hundreds of possible Tau-derived peptides. Peptides have been
shown to rapidly induce the misfolding and aggregation of tau in vitro and in mammalian cells. Here we
propose to test and rank the propensity of Tau aggregation induction by each protease-cleaved Tau peptide
after incubation with full-length recombinant Tau isoforms and subsequently capture aggregate gross
morphology using transmission electron microscopy (TEM). Intracellular signaling activity by Tau peptides will
be detected in cell culture to further characterize each peptide. Peptides inducing full-length Tau protein to
aggregate or having active cellular signaling properties may implicate protease components dysregulated in
disease. Because many known cleavage sites on Tau protein remain uncharacterized, this study aims to
collect preliminary data for future funding and will begin groundwork for long-term research of proteolytic post-
translational modification to identify those sites on Tau which may produce toxic peptides in neurons.

## Key facts

- **NIH application ID:** 10728202
- **Project number:** 1R21AG083630-01
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** Carol J. Huseby
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2023-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10728202

## Citation

> US National Institutes of Health, RePORTER application 10728202, Tau protein proteolysis signaling in Alzheimer's disease (1R21AG083630-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10728202. Licensed CC0.

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