# Targeting Rho Kinases for Alzheimer's disease Therapeutics

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $371,250

## Abstract

Project Summary
Current Alzheimer's disease (AD) therapies predominantly focus on amyloid-β (Aβ) peptides, but biomarker
studies indicate that Aβ effects may be maximal before onset of clinical symptoms. Downstream of Aβ,
synapse loss and intracellular accumulation of the microtubule-associated protein tau correlate strongly with
cognitive decline, yet few therapeutic strategies target these mechanisms. Presently, twenty-nine kinase
inhibitors are used to treat human diseases, and out of these, two are pan- Rho-associated protein kinases
(ROCK) 1 and 2 inhibitors. In the mid-2000s, the ROCKs were identified as putative translational targets to
curb Aβ production. However, progress on this exciting avenue languished due to three critical barriers: 1) the
lack of connection between ROCKs and AD pathogenesis beyond mechanisms tied to Aβ generation, 2) the
lack of genetic models to test the role of ROCK1 or ROCK2 in AD mice, and 3) the lack of kinase inhibitors
offering high ROCK-selectivity and brain penetrance. We aim to overcome these barriers with new data linking
ROCKs to structural plasticity changes in AD progression and employing new ROCK1 and ROCK2 conditional
knockout mice as well as novel pan- and isoform-selective ROCK inhibitors that exhibit high bioavailability and
brain penetrance with no gross side-effects. In Aim 1, we will address the contribution of ROCK1 and ROCK2
to Aβ-induced dendritic structure degeneration. In Aim 2, we will test the effects of chronic ROCK inhibition in
mouse models of AD, and in Aim 3, we will elucidate the mechanisms by which ROCK1 and ROCK2 mediate
tau protein homeostasis and autophagy induction.

## Key facts

- **NIH application ID:** 10173580
- **Project number:** 5R01AG054719-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Jeremy H. Herskowitz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $371,250
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173580

## Citation

> US National Institutes of Health, RePORTER application 10173580, Targeting Rho Kinases for Alzheimer's disease Therapeutics (5R01AG054719-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10173580. Licensed CC0.

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