# Novel Acetylated Tau Immunotherapy for Alzheimer's disease

> **NIH NIH F32** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $70,082

## Abstract

PROJECT SUMMARY/ABSTRACT:
Alzheimer’s disease (AD) is a fatal, age-progressive neurodegenerative disease affecting nearly 6 million
patients in the US. Currently, there is no cure for AD, and existing clinical trials have largely failed. This calls
for the need to investigate new avenues to combat this disease. Recently, we and others have focused on
post-translational modifications (PTM) of tau protein that mediate progression of tauopathies including AD. We
identified acetylated tau as a key feature of nearly all AD patients and elucidated several pathways through
which tau acetylation mediates toxicity including insoluble tau fibril formation, promoting aberrant tau hyper-
phosphorylation, and causing dissociation of tau from microtubule (MTs). Furthermore, loss of key
deacetylases that suppress tau acetylation including a sirtuin (SIRT1) and in our unpublished studies, the
deacetylase HDAC6, is sufficient to exacerbate AD phenotypes in mice. We hypothesize that acetylated tau
(Ac-Tau) represents a novel pathological strain that can be exploited therapeutically. Here, we will employ a
first-of-its-kind preclinical immunotherapy study to target acetylated tau in an AD mouse model
characterized by combined tau tangles and amyloid plaques. This model will better recapitulate human AD
in which both tau and amyloid beta pathologies are present. By employing diverse, interdisciplinary
approaches afforded by excellent UNC core facilities and collaborations, we will validate whether Ac-Tau
immunotherapy can rescue AD-like neurodegeneration and cognitive decline. In Aim 1, we will screen >30
candidate monoclonal mouse antibodies via a newly developed in vitro high-throughput microscopy pipeline in
tau-transfected cells to determine which candidate acetyl-tau antibodies against two specific sites (commonly
observed in AD patients; K280 and K311) are most suitable for immunotherapy based on specificity and
sensitivity for Ac-Tau. Preliminary data has confirmed that several antibodies are highly specific and promising.
Given that Ac-Tau has been suggested as a disease-specific marker, we will investigate the utility of the Ac-tau
antibodies for the detection of CSF-tau as a new AD biomarker. In Aim 2, using our most promising candidate
antibodies for Ac-Tau, we will carry out an in vivo Ac-Tau immunotherapy trial in plaque/tangle bearing
PS19/5xFAD mice at both early, preventative (3-6 months) and late (6-9 months) timepoints. We will perform
biochemical and histological assays to assess key hallmarks of AD pathology and neurodegeneration followed
by a rigorous evaluation of cognition, learning, and survival following Ac-Tau based immunotherapy. This
project outlines the first in vivo immunotherapy study targeting Ac-Tau, which could potentially provide a new
AD therapeutic and prognostic biomarker for use in the clinic. Furthermore, this proposal outlines a
collaborative, comprehensive, and valuable post-doctoral training opportunity.

## Key facts

- **NIH application ID:** 10428347
- **Project number:** 5F32AG072826-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Miles Richard Bryan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $70,082
- **Award type:** 5
- **Project period:** 2021-04-27 → 2024-04-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428347

## Citation

> US National Institutes of Health, RePORTER application 10428347, Novel Acetylated Tau Immunotherapy for Alzheimer's disease (5F32AG072826-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10428347. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*