# Targeting Kinesin-5 Activity for treatment of Alzheimer's disease

> **NIH NIH F99** · UNIVERSITY OF COLORADO DENVER · 2020 · $18,400

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer's disease (AD) currently affects more than 5 million Americans and is a significant burden for
patients, caregivers, and our healthcare system. Currently, there is no known cure for AD, and approved
therapies do not reverse the underlying pathogenesis or inhibit disease progression. Amyloid deposits and
their associated amyloid beta oligomers (Aβ) are linked to multiple cellular dysfunctions in the brains of AD
patients and in animal and cell culture models of AD. Some of these dysfunctions include microtubule
instability, loss of dendritic spine density, and depressed hippocampal long-term potentiation (LTP). Many
hypotheses have been put forward to explain the routes by which Aβ contributes to these phenotypes.
However, a unified mechanistic understanding has not yet been achieved. This project builds on previous
studies that have shown that Aβ inhibits the activity of a select set of microtubule motor proteins. Among them,
Kinesin-5/EG5/KIF11 is of particular interest due to its diverse functions, which include regulating microtubule
stability, microtubule polymerization, and dendritic architecture, all of which are negatively impacted by Aβ.
Based on these findings, the long-term goal of this project is to determine whether Kinesin-5 activity may
serve as an effective target for preventing or reversing A β -induced AD phenotypes: 1) by
overexpressing Kinesin-5 to maintain its activity, or 2) by using small molecule drugs we identified in a
screen that block Aβ-mediated inhibition of Kinesin-5 activity. In order to address these goals we are
using a mouse model system in combination with cell culture and biochemical tests that aim to 1) Determine
whether Kinesin-5 overexpression improves learning and memory in a wild-type mouse without AD pathology
and whether Kinesin-5 overexpression rescues Aβ-induced AD phenotypes in the an AD mouse model; 2)
Determine whether Kinesin-5 overexpression improves long-term potentiation (LTP) and whether deficits in
LTP caused by Aβ are rescued by Kinesin-5 overexpression; and 3) Determine whether Kinesin-5
overexpression impacts neural process outgrowth, spine density, and morphology in wild-type and 5xFAD
mice. Our proposed research will also provide an increased understanding of the role of Kinesin-5 activity in
regulating diverse neuronal processes. The clinical significance of this work comes from the identification of
underlying mechanisms linked to aberrant cellular functions that may uncover an entirely new therapeutic
approach to AD. The innovative aspects of this project are rooted in the identification of Kinesin-5 as a
potential therapeutic target for the treatment of AD and include: 1) interrogating of as yet uncharacterized
functions of Kinesin-5 in learning, memory, and AD-related phenotypes; and 2) pursuing an entirely new
avenue of investigation into desperately needed AD treatments using Kinesin-5 activity as a therapeutic target. !

## Key facts

- **NIH application ID:** 9999991
- **Project number:** 5F99NS115330-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Esteban M Lucero
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $18,400
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999991

## Citation

> US National Institutes of Health, RePORTER application 9999991, Targeting Kinesin-5 Activity for treatment of Alzheimer's disease (5F99NS115330-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999991. Licensed CC0.

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