# The Influence of Tau Post-Translational Modifications on the Propagation of Tau Pathology in Alzheimer's Disease

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $172,800

## Abstract

Project Summary/Narrative
 This K08 Mentored Clinical Scientist Research Career Development Award application investigates the
role of tau post-translational modifications on the cellular processes involved in the stereotyped spreading of
tau pathology that occurs as Alzheimer’s disease progresses. The cellular mechanisms underlying this process
include the cell-to-cell propagation of pathologic tau from a donor cell to a recipient cell, escape from the
endosomal compartment in the recipient cell, and subsequent seeding of tau aggregation in the cytoplasm.
Previous studies published in the literature, as well as preliminary data related to this project, suggest that tau
post-translational modifications, especially phosphorylations and acetylations, influence these processes.
 The overall hypothesis of the project is that tau post-translational modifications found on pathologic
tau in Alzheimer’s disease influence the cellular mechanisms involved in the spreading of tau pathology. The
specific aims of the project focus on investigating the impact of disease-associated tau post-translational
modifications on 1) the cell-to-cell propagation of tau, 2) the endosomal escape of tau, and 3) the seeding
activity of tau. The research strategy for this project uses human induced pluripotent stem cell-derived
neurons to study the processes outlined in the specific aims, and mutations mimicking post-translational
modifications (pseudophosphorylations and pseudoacetylations) will be used to assess the contribution of
defined combinations of specific residues. Specific Aim 1 uses an expression construct with the wildtype or
mutant tau sequences to identify donor and recipient cells by flow cytometry to assess cell-to-cell propagation.
Specific Aim 2 uses treatment of neurons with wildtype or mutant recombinant tau proteins and evaluation of
endosomal membrane integrity and tau endosomal escape using immunocytochemistry with galectin-3 staining
and a split luciferase assay, respectively. Specific Aim 3 uses tau Förster resonance energy transfer (FRET)
biosensor cell models to detect tau seeding activity of the wildtype or mutant recombinant tau proteins or
Alzheimer’s disease-derived tau preparations with or without in vitro dephosphorylation and/or deacetylation.
 The career development plan of this proposal is designed to prepare the applicant for independence
as a scientist. The applicant will take courses that provide a conceptual framework for design, performance,
and analysis of the experiments described above. Scientific communication skills will be further developed by
coursework and experience in writing manuscripts/grants and presenting the results at scientific meetings. The
applicant had assembled a team of mentors, both the primary mentor and Scientific Advisory Board, to assist
in the applicant’s development over the course of the project. The combination of the research experience,
career development activities, and mentorship the applicant recei...

## Key facts

- **NIH application ID:** 10837824
- **Project number:** 5K08AG078341-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JOHN R DICKSON
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $172,800
- **Award type:** 5
- **Project period:** 2022-08-04 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837824

## Citation

> US National Institutes of Health, RePORTER application 10837824, The Influence of Tau Post-Translational Modifications on the Propagation of Tau Pathology in Alzheimer's Disease (5K08AG078341-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10837824. Licensed CC0.

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