# Phosphorylation-dependent human tau release

> **NIH NIH R15** · OHIO UNIVERSITY ATHENS · 2020 · $453,000

## Abstract

Neurofibrillary tangles (NFT) are a hallmark of Alzheimer's disease (AD) and related
dementias. NFTs are of growing biomedical interest as the temporal and spatial pattern of NFT
appearance in human brain correlates well with AD progression. The tangle is composed of
microtubule associated protein tau, which can be hyper-phosphorylated and aggregated.
Indeed, tau protein purified from the brains of AD patients is hyper-phosphorylated, which has
led to investigations of the role of tau phosphorylation in mediating neurodegeneration.
 Alzheimer's pathogenic mechanisms still remain elusive. Recently, an intriguing concept of
prion-like spreading of tau has emerged, which has the potential to transform AD research. A
prion-like mechanism involving the transfer of hyper-phosphorylated tau between synaptically
connected neurons underlies the seeding and spread of tau pathology. New insights into the
molecular mechanisms of tau propagation will uncover potential therapeutic targets for slowing
or even halting AD progression.
 Hyper-phosphorylation of tau is also known to be involved in tau release, causing its cell-to-cell propagation. However, there is still a significant gap in understanding how phosphorylation
regulates tau release. We hypothesize that individual phosphorylation sites will differentially
affect tau release and that studying this phenomena will uncover a currently unexplored
network of endogenous protein kinases that act to regulate tau release by phosphorylating
specific residues on tau. In particular, it is not known what phosphorylation sites of tau (pTau)
are crucial for its release and kinases have yet to be identified for their role in tau release - a
recognized seminal step in the prion-like spreading of tau protein.
 In Aim 1, we will study the role of specific phosphorylation sites of tau on its release. pTau
sites to be examined will be primarily in proline-rich domain (PRD) and C-terminal region of tau
as ~75% of disease associated pTau sites are found in these regions. In Aim 2, we will
examine 5 kinases for their role in tau release as they are known to phosphorylate amino acids
in PRD and C-terminal regions. Aim 3 will test if activity-driven endogenous hTau release is
modulated by phosphorylation of tau at specific amino acids using a human neural cell line
(ReNCell) endogenously expressing hTau. Our approach with Drosophila (Aims 1 & 2) and
human neuronal culture models (Aim 3) will also provide excellent opportunities for training
and mentoring both undergraduate and graduate students.

## Key facts

- **NIH application ID:** 10046878
- **Project number:** 1R15AG065925-01A1
- **Recipient organization:** OHIO UNIVERSITY ATHENS
- **Principal Investigator:** DAEWOO LEE
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,000
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046878

## Citation

> US National Institutes of Health, RePORTER application 10046878, Phosphorylation-dependent human tau release (1R15AG065925-01A1). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/10046878. Licensed CC0.

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