# Mechanistic insights into the link between the A152T risk variant and tauopathy

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2024 · $385,785

## Abstract

PROJECT SUMMARY/ABSTRACT
Pathogenic mutations in the tau gene (MAPT) are linked to the onset of tauopathy, but the A152T mutation is
unique in acting as a risk factor for a range of disorders including Alzheimer’s disease (AD), progressive
supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). As an
unconventional approach to investigate the role of tau in neurodegeneration, we reasoned that understanding
how the A152T variant modulates risk of AD and related disorders could reveal a common disease
mechanism(s), uncovering novel strategies to increase resilience to tau toxicity and modify disease
phenotypes in patients. Given the introduction of a new potential phosphoepitope, we questioned whether the
A152T variant might impact disease risk through altered phosphorylation of tau on either T152 or the
neighboring T153 residue. A series of novel antibodies were generated to test this idea, which revealed
significant accumulation of soluble tau species hyperphosphorylated on T153 (pT153) in postmortem brain
tissue from A152T carriers compared to noncarriers, as well as in mice expressing A152T-AAV. Therefore the
current project will investigate the overall hypothesis that the A152T variant modulates disease risk
through enhanced accumulation and increased solubility of pT153-positive tau, which subsequently
primes tau for downstream pathological phosphorylation events and is critical for tau-mediated
toxicity. Of note, phosphorylation on T153 and tau’s other serine/threonine-proline motifs has been shown to
be required for tau toxicity, although the extent to which pT153 contributes to tau toxicity remains untested. In
elucidating the pattern of pT153 deposition throughout the brain in A152T carriers and noncarriers, the
proposed studies will determine if pT153-positivity coincides with neurodegeneration. Using site-directed
mutagenesis and somatic brain transgenesis, we will determine whether pT153 is required for tau toxicity in
vivo. Finally, incorporating rapidly evolving technology that is enabling acquisition of global gene expression
profiles at the single cell level, we will assess whether expression of the A152T variant differentially impacts
the transcriptome of individual cell populations. We anticipate that in uncovering the mechanisms by which
A152T influences risk of tauopathy, and deciphering the involvement of pT153 in tau toxicity, the current
project could identify novel approaches to block tau-mediated neurodegeneration in AD and related disorders.

## Key facts

- **NIH application ID:** 11353349
- **Project number:** 7R01AG063780-06
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Casey N Cook
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,785
- **Award type:** 7
- **Project period:** 2020-04-15 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11353349

## Citation

> US National Institutes of Health, RePORTER application 11353349, Mechanistic insights into the link between the A152T risk variant and tauopathy (7R01AG063780-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11353349. Licensed CC0.

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