# Pathogenic Roles for Microtubule Stabilization Pathways in Alzheimer's Disease

> **NIH NIH R56** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $754,997

## Abstract

Summary
The two main neuropathological hallmarks associated with Alzheimer’s disease (AD) are amyloid beta plaques
and intracellular neurofibrillary tangles comprised of hyperphosphorylated variants of the microtubule binding
protein tau. These deposits lead to abnormal cellular structure and loss of synapses, both of which strongly affect
behavior and memory. However, the pathogenic mechanisms that trigger the formation of these deposits and
early synaptic dysfunction are still poorly understood and lack of this knowledge is a hurdle for the development
of effective therapeutic strategies. Tubulin undergoes numerous post-translational modifications (PTMs) that
affect both microtubule stability and associated proteins, including tau and microtubule-dependent motors. The
tubulin tyrosination/detyrosination (Tyr/deTyr) cycle occurs when the C-terminal tyrosine of α-tubulin residing in
a microtubule is episodically cleaved and then returned by a tubulin-tyrosine-ligase (TTL). Importantly,
detyrosinated tubulin can be irreversibly converted by carboxypeptidases 1/4/6 to delta 2 tubulin (D2) by
cleavage of the penultimate amino acid of glutamic acid. This change permanently removes D2 from the cycle.
D2 accumulation is therefore a hallmark of microtubule longevity, although its effects on microtubule stability,
tau hyperphosphorylation and synaptotoxicity are completely unknown.
 This proposal is designed to test the central hypothesis that inhibition of tubulin re-tyrosination
and accumulation of D2 affect microtubule dynamics and are molecular drivers of tau
hyperphosphorylation, defective axonal transport and mitochondria dysfunction, with severe direct
consequences on neurotransmission. Our proposed studies are novel and highly significant, as they will
examine a new role for dysregulation of the Tyr/deTyr tubulin cycle in promoting tau hyperphosphorylation and
AD pathology in primary hippocampal neurons, mice and a human model of familial AD. The hypothesis relies
on our preliminary data showing that: 1) defects in tubulin re-tyrosination correlate with AD progression and tau
hyperphosphorylation in sporadic and familial AD; 2) loss of tubulin re-tyrosination promotes activation of the
stress sensor and tau kinase AMPK, tau hyperphosphorylation and synaptic injury; 3) synaptic dynamic MTs
play critical roles in synaptic and structural plasticity.
 This proposal relies on a multidisciplinary effort to examine the in vitro and in vivo mechanisms by which
premature tubulin longevity may drive tau hyperphosphorylation and AD-related synaptic dysfunction. The work
has the potential to identify novel targets that may be modulated in drug therapies aimed at rescuing cognitive
decline in sporadic and familial forms of AD.

## Key facts

- **NIH application ID:** 10427868
- **Project number:** 2R56AG050658-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Francesca Bartolini
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $754,997
- **Award type:** 2
- **Project period:** 2016-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427868

## Citation

> US National Institutes of Health, RePORTER application 10427868, Pathogenic Roles for Microtubule Stabilization Pathways in Alzheimer's Disease (2R56AG050658-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10427868. Licensed CC0.

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