# Dual CHIP Functions Control Tau Triage In Alzheimer's Disease

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $619,744

## Abstract

PROJECT SUMMARY/ABSTRACT
The accumulation of aggregated tau protein in the brain is a defining feature of Alzheimer’s disease (AD) and a
logical therapeutic target to prevent AD progression. Genetic evidence in mice strongly supports the notion that
tau promotes cognitive deficits in AD. While anti-aggregation and immunotherapy approaches have emerged
as potential strategies to reduce tau aggregation in the brain, these target late-stage tau intermediates. Much
less is known about the early-stage events that give rise to tau aggregates in otherwise healthy neurons, a
time period in which chaperone-dependent refolding acts in a compensatory manner to restore tau function as
a critical microtubule (MT) stabilizing factor. We seek to define these early-stage tau triage decisions since
clinically targeting tau in this earlier window is highly desirable to prevent tau accumulation, particularly in
asymptomatic individuals years to decades from disease onset. The C-terminus of heat shock 70-interacting
protein (or CHIP) plays a central role in orchestrating protein quality control. While most prior studies have
pointed to CHIP’s E3 ligase activity as a principal mediator of client substrate degradation including tau,
studies now indicate that CHIP contains a poorly understood intrinsic chaperone function that operates
completely independent of its E3 ligase activity. Genetic studies of spinocerebellar ataxia 16 (SCAR 16)
patients, a rare neurodegenerative disorder, showed that loss of CHIP co-chaperone activity alone is sufficient
to cause neurodegeneration and cognitive dysfunction. These prior studies, combined with our compelling new
preliminary data showing that CHIP directly binds and chaperones tau to facilitate its dephosphorylation,
provide strong support for a new model of CHIP-mediated tau triage. We hypothesize that CHIP prevents
aberrant tau modifications and aggregation, restores normal tau function and MT stabilization, and
ameliorates AD-related cognitive decline. In Aim-1, we will dissect CHIP’s dual functions as a regulator of
tau function and phosphorylation using biochemical and biophysical assays in vitro. These studies will provide
new mechanistic insights into how CHIP targets and repairs abnormal tau species. In Aim-2, we will explore a
novel role for CHIP in mediating neuroprotection via the stabilization of MTs. We will test the requirements for
CHIP co-chaperone activity in maintaining MT integrity and hence promoting survival in neurons that would
otherwise undergo degeneration. Finally, in Aim-3, we will test the clinical implications of CHIP co-chaperone
function in restoring cognition in an animal model of AD. Overall, our proposal is significant because it will
illuminate the early-stage events that determine how tau is initially processed and triaged. It is also innovative
because it is the first to highlight dual molecular functions of CHIP that are relevant to tau pathogenesis and
the progression of this devastating di...

## Key facts

- **NIH application ID:** 9876969
- **Project number:** 5R01AG061188-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Todd Jonathan Cohen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $619,744
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876969

## Citation

> US National Institutes of Health, RePORTER application 9876969, Dual CHIP Functions Control Tau Triage In Alzheimer's Disease (5R01AG061188-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9876969. Licensed CC0.

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