# Treating neurotoxicity and cognitive deficits due to hyperphosphorylated tau.

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $608,361

## Abstract

PROJECT SUMMARY (Description)
Hyperphosphorylated tau is the major component of neurofibrillary tangles existing in the brains of Alzheimer’s
Disease patients, but whether soluble hyperphosphorylated tau oligomers are already toxic to neurons, and if
so, through what mechanisms, have remained unclear. This is largely due to the lack of experimental system
to tackle these questions directly. This project will test the hypothesis that hyperphosphorylated tau oligomers
promote neurotoxicity before the formation of insoluble tau fibrils, which is amplified by Ab peptides and/or the
ApoE4 allele, but either apomorphine and raloxifene treatment mitigates these deleterious effects. This project
has three specific aims.
Aim 1 will compare the effects of intrahippocampal injection of tau and hyperphosphorylated tau (hyper-ptau) in
wildtype and AD-mutant mice (J20 and ApoE KI). We will also compare the onset of behavioral/histological deficit
and insoluble tau fibrils in these mice after intrahippocampal injection.
Aim 2 will test the effects of hyper-ptau on the viability, mitochondrial functions, and axonal trasnport of cultured
neurons. We will also confirm mitochondrial dysfunctions after brain injection of hyper-ptau in vivo.
Aim 3 will test the protective effects of apomorphine and raloxifene in preventing hyper-ptau-induced toxicity
and cognitive deficits in mice. Both compounds attenuates ptau aggregation in vitro and have a high potential
to be repurposed for clinical treatment of AD.

## Key facts

- **NIH application ID:** 10933572
- **Project number:** 5R01NS135693-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Chia-Yi Kuan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $608,361
- **Award type:** 5
- **Project period:** 2023-09-22 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933572

## Citation

> US National Institutes of Health, RePORTER application 10933572, Treating neurotoxicity and cognitive deficits due to hyperphosphorylated tau. (5R01NS135693-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10933572. Licensed CC0.

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