# Cellular and Molecular Mechanisms of Neurotoxicity and Cognitive Deficits Due to Hyperphosphorylated Tau

> **NIH NIH F32** · UNIVERSITY OF VIRGINIA · 2024 · $73,828

## Abstract

PROJECT SUMMARY/ABSTRACT
Hyperphosphorylation of tau, a microtubule associated protein, is a hallmark of neurofibrillary tangles (NFT)
that correlate with cognitive impairment in Alzheimer's disease (AD) patients. While tau is natively unfolded,
it has 80+ phosphorylation sites, and the alteration from tau to phosphorylated tau (ptau) to
hyperphosphorylated tau (hyper-ptau) changes its biophysical properties and transforms from soluble
oligomers to sarkosyl (detergent)-insoluble NFTs. Growing evidence suggests that hyper-ptau oligomers are
already neurotoxic, but there have been few experimental systems to directly test this idea and develop
therapeutic strategies. In preliminary work, the Kuan lab has generated recombinant hyper-ptau
oligomers using the Protein Interaction Module-Assisted Function X (PIMAX) system and tested their
effects in vitro and in vivo using the mouse model system. The lab has found that intrahippocampal
injection of hyper-ptau induces neuroinflammation, neuronal cell death, and cognitive deficits similar to AD
patients. These findings establish that hyper-ptau oligomers directly promote neurotoxicity and cognitive
dysfunction. The objective of my proposal is to further investigate the molecular and physiological effects of
hyper-ptau oligomers on brain function using a combination of hypothesis-free transcriptomic profiling and
neurophysiology approaches. I hypothesize that hyper-ptau oligomers induce neuroinflammation and
alters synaptic plasticity of hippocampal neurons, leading to neurodegeneration and altered
cognition. Aim 1 will characterize the cellular and molecular effects of hyper p-tau oligomers in vivo using
unbiased single-cell transcriptomic profiling. Aim 2 will investigate the impact of hyper p-tau oligomers on
hippocampal function by measurement of long-term potentiation in brain slices. Completion of these aims will
help to elucidate the mechanisms underlying the neurotoxicity and cognitive effects of hyperphosphorylated
tau, informing future treatment strategies of AD and tauopathies. In addition, it will provide me with valuable
mentored-training in areas I lack expertise to continue my development as a physician-scientist and better
prepare me to become an independent investigator.

## Key facts

- **NIH application ID:** 10994896
- **Project number:** 1F32AG089892-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Duy Phan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $73,828
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10994896

## Citation

> US National Institutes of Health, RePORTER application 10994896, Cellular and Molecular Mechanisms of Neurotoxicity and Cognitive Deficits Due to Hyperphosphorylated Tau (1F32AG089892-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10994896. Licensed CC0.

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