# Regulation of Pathological Tau Transmission by Soluble Tau Post-Translational Modifications

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $671,674

## Abstract

Accumulating evident support intercellular transmission and subsequent amplification of pathological tau as a
key mechanism for the progression of Alzheimer’s disease (AD) and other tauopathies. Blocking this
transmission process is a promising therapeutic strategy to slow down disease progression. However, the
molecular mechanisms that regulate pathological tau transmission remains largely unknown. Previous studies
of tau transmission have been focused on pathological tau or the ‘seed’ itself. But, the amplification of
pathological tau requires both the ‘seed’ and soluble tau, the ‘substrate’. What has generally been ignored is
the potential effect of soluble tau on the amplification of pathological tau. Our preliminary study demonstrated
that soluble α-synuclein (a-syn) post-translational modifications (PTMs) would dramatically affect the
amplification of pathological a-syn, which highlights for the first time that PTMs on soluble protein would affect
amplification of the corresponding pathological protein. Since many PTMs were identified on soluble tau, we
hypothesize that soluble tau PTMs will also affect pathological tau amplification. Indeed, our preliminary data
demonstrated that soluble tau acetylation could dramatically modulate the amplification of pathological tau
prepared from AD brains (AD-tau). More interestingly, this effect is highly pathological tau conformation
dependent. Pathological tau from corticobasal degeneration brains (CBD-tau) shows very different responses
to soluble tau PTMs compared with AD-tau. Here, we propose to systematically explore how soluble tau PTMs
would modulate the amplification of pathological tau in AD and other tauopathies.
Firstly, PTMs on soluble tau from tauopathy brains has not been systematically identified and quantified.
Therefore, we propose to systematically identify and quantify soluble tau PTMs in AD and other tauopathies by
LC-MS/MS. Secondly, we will explore how soluble tau PTMs and PTM combinations would affect the
amplification of pathological tau in AD and other tauopathies. Thirdly, the effects of soluble tau PTMs are highly
pathological tau conformation dependent. Therefore, we propose to evaluate whether pathological tau in
different disease subtypes, brain regions, and cell types (neurons and glial cells), would have different
responses to soluble tau PTMs. Fourthly, it has been shown that different intracellular environment in neurons
and glial cells would affect the amplification of pathological proteins. We propose to test whether different
intracellular environment would also change the effect of soluble tau PTMs. Finally, the effects of soluble tau
PTMs on AD-tau amplification will be evaluated in mouse. In summary, the proposed study represents the first
to systematically explore how soluble tau PTMs would affect the amplification of pathological tau in AD and
other tauopathies, which is a novel mechanism that modulates tau transmission. Successful performance of
the proposed ...

## Key facts

- **NIH application ID:** 10656522
- **Project number:** 5R01NS128964-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Chao Peng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $671,674
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656522

## Citation

> US National Institutes of Health, RePORTER application 10656522, Regulation of Pathological Tau Transmission by Soluble Tau Post-Translational Modifications (5R01NS128964-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10656522. Licensed CC0.

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