# The role of microtubule network in a mouse model of Alzheimer’s disease

> **NIH NIH R03** · RUTGERS, THE STATE UNIV OF N.J. · 2024 · $157,000

## Abstract

PROJECT SUMMARY
Alterations of a microtubule-binding protein tau are one of hallmarks of Alzheimer’s disease (AD), with
progressive memory loss being one of its major symptoms. Tau is a microtubule-associated protein, which
stabilizes microtubules. Tau is key facilitator of neuronal transport, mediated by microtubules, and regulation of
the microtubule cytoskeleton and microtubule-mediated transport is implicated in AD. A disruption of the
microtubule network, which might be caused by Tau loss of function, is observed in AD, contributing to memory
loss, but it is not clear what is the role of microtubule stability/instability and microtubule-mediated neuronal
transport. Activity-dependent changes, including dynamic rearrangement of microtubules and strengthening of
synaptic connections, are important for memory formation. Here we propose to examine how microtubule
stability/instability are affected in mice modeling some of the AD mechanisms. We and others showed that
activity-dependent changes in microtubule stability are critical for synapse function and memory and are
disrupted in normal aging. We will focus on the role of a phospho-protein stathmin, which function to bind
tubulin, disassemble microtubules and regulate microtubule dynamics is dependent on its phosphorylation. We
found that stathmin regulates memory consolidation: changes in the microtubule-destabilizing activity of
stathmin cause rapid biphasic shifts in microtubule stability in the hippocampus synapses following learning.
Moreover, stathmin mutations disrupt learning-dependent biphasic changes in microtubule stability, synaptic
localization of GluA2 subunit of AMPARs, synaptic plasticity and memory. We will examine whether stathmin-
dependent and microtubule-mediated changes in GluA2 synaptic localization improve or worsen memory
deficits in a tau-related AD model. Overall, our work will characterize a role in memory in an AD model for a
novel activity-dependent signaling pathway where stathmin-microtubule interactions regulate microtubule-
mediated GluA2 synaptic localization. We will study how stathmin may affect a tau-related AD model, Tau
P301S (PS19) mice. We previously showed that stathmin deletion makes microtubules hyperstable and Stat4A
makes microtubules unstable. Our hypothesis is that activity-dependent stathmin-microtubule interactions at
the synapse regulate microtubule stability, GluA2 localization and memory in a Tau mouse model of
Alzheimer’s disease. In Aim 1 we will study activity-dependent changes in synaptic microtubules and GluA2 in
Tau P301S (PS19) mice with loss-of-function or gain-of-function stathmin mutants. In Aim 2, we will study the
effects of the stathmin mutants on synaptic plasticity and memory in Tau P301S (PS19) mice. These
experiments will examine whether changes in microtubule stability/instability affect memory in PS19 mice and
suggest possible microtubule involvement in the development of AD memory deficits. Positive outcomes from
these s...

## Key facts

- **NIH application ID:** 10993466
- **Project number:** 1R03AG085121-01A1
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** Juan Marcos Alarcon
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $157,000
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993466

## Citation

> US National Institutes of Health, RePORTER application 10993466, The role of microtubule network in a mouse model of Alzheimer’s disease (1R03AG085121-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10993466. Licensed CC0.

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