# Hyperphosphorylated tau and the molecular mechanisms of tauopathy

> **NIH NIH RF1** · MICHIGAN STATE UNIVERSITY · 2022 · $1,337,894

## Abstract

Hyperphosphorylated tau and the molecular mechanisms of tauopathy
Tauopathies are neurodegenerative disorders sharing the common pathology of the tau protein in the central
nervous system. The most prominent tauopathy is Alzheimer’s disease (AD) that affects nearly 6 million
Americans and more than 30 million people worldwide. Animal and cell studies demonstrated that soluble,
oligomeric hyperphosphorylated tau is toxic to cells, and can transmit in a prion-like fashion in the brain. However,
how hyperphosphorylation converts tau into a cytotoxic species, and how hyperphosphorylated tau exerts its
cytotoxicity are unclear. As such, development of efficacious tauopathy therapeutics remains a formidable
challenge.
 This R01 project aims to use a recombinant hyperphosphorylated tau (p-tau) as the model to examine
the molecular mechanisms underlying tauopathies. Specifically, we wish to answer two major questions: how
does hyperphosphorylated tau damage or kill cells? And what makes tau a cytotoxic species? We will perform
proteomics studies to identify targets of p-tau that may lead to the realization of novel druggable targets for future
therapeutics design. We will also pinpoint the phosphorylatable residues of the tau protein that, upon
modification, drive the genesis and transmission of a pathogenic species. Finally, we have found that the
formation of cytotoxic p-tau fibrils is subjected to the regulation of the ApoE lipoprotein and of selective
metabolites of cholesterol. Biochemical and cell studies are to be performed to unravel the molecular details,
which will facilitate our understanding of how different ApoE alleles contribute to the development of Alzheimer’s
disease, as well as how cholesterol metabolism is mechanistically linked to this devastating disease.

## Key facts

- **NIH application ID:** 10447253
- **Project number:** 1RF1AG077475-01
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Min-Hao Kuo
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,337,894
- **Award type:** 1
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447253

## Citation

> US National Institutes of Health, RePORTER application 10447253, Hyperphosphorylated tau and the molecular mechanisms of tauopathy (1RF1AG077475-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10447253. Licensed CC0.

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