# Tau acetylation in Alzheimer's disease

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $506,388

## Abstract

The cognitive decline in Alzheimer's disease (AD) correlates with tau pathology or CSF tau. However, the
pathogenic tau species and the mechanisms underlying tau toxicity in AD remain elusive. Our recent study
points to important pathogenic roles for aberrantly acetylated tau (ac-tau) species, whose levels are elevated in
NFTs, and the elevation is associated with cognitive impairment in AD. A critical trigger of tau-mediated toxicity
in AD is elevated somatodendritic tau. We showed that tau acetylation on K274 and K281 destabilizes the
barrier in the axon initial segment (AIS) and elevates levels of somatodendritic tau. Mice expressing mutant tau
that mimics acetylation (KQ) exhibited impaired synaptic plasticity and spatial memory. Our study further linked
tau-mediated synaptic plasticity impairment with deficiency in KIBRA, post-synaptic scaffolding protein. While
KIBRA is reduced in AD brains, elevating KIBRA expression prevented KQ-induced LTP deficits in rat neurons.
We propose to further dissect the mechanisms underlying ac-tau-mediated deficits in synaptic plasticity and
memory by combining human neuron and mouse models. In Aim 1, we will focus on the effects of ac-tau on
the AIS, which plays a critical role in restricting axonal protein from somatodendritic compartments in human
neurons. We will use our newly established inducible pluripotent stem cells (iPSCs)-derived human neuron
platform and CRISPR/cas9 genomic editing to establish isogenic lines that express acetyl-mimicking tau at
endogenous levels. We will then collaborate with Dr. Ke Xu and use stochastic optical reconstruction
microscopy (STORM) to image AIS structural proteins and tau distribution in axons and dendrites of human
neurons at single-molecule resolution. In Aim 2, we will directly determine whether ac-tau gains access to
dendritic spines by destabilizing the AIS using a combination of STORM and live imaging. In human iPSC
neurons, we will assess the effects of ac-tau on microtubule dynamics and stability, particularly at AIS, using
fluorescence recovery after photobleaching. We will then compare the extent to which WT and KQ tau cross
the AIS and determine whether restoring AIS barrier function specifically using caged taxol would normalize
tau distribution. In Aim 3, we will dissect the post-synaptic mechanisms underlying tau-mediated synaptic
plasticity and cognition. To determine if deficiency in KIBRA is a driver in tau-mediated synaptic deficits, we
test if lowering KIBRA levels is sufficient to cause tau-mediated synaptic deficits by deleting one allele of
KIBRA in mice expressing human wildtype tau. Various domains of KIBRA interact directly with postsynaptic
proteins, including PICK1, synaptopodin, dendrin, dynein, and PKMζ, to regulate actin cytoskeleton and/or
AMPAR trafficking. Using KIBRA mutants containing specific signaling domains, we propose to identify which
KIBRA-mediated signaling plays a critical role in tau-mediated synaptic toxicity. By combini...

## Key facts

- **NIH application ID:** 10153606
- **Project number:** 5R01AG054214-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Li Gan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $506,388
- **Award type:** 5
- **Project period:** 2018-09-13 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153606

## Citation

> US National Institutes of Health, RePORTER application 10153606, Tau acetylation in Alzheimer's disease (5R01AG054214-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10153606. Licensed CC0.

---

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