PAK1 inhibitor NVS‐PAK1‐1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice
p21-activated kinase 1 (PAK1) inhibitors prevent oligomeric amyloid beta (oAβ) and oligomeric tau-induced spine loss and dendritic degeneration in cultured mouse hippocampal neurons. NVS-PAK1-1, a selective PAK1 inhibitor, protects against oAβ-induced spine loss in a dose-dependent manner (EC<sub>50</sub> = 2 nM). Oral administration of NVS-PAK1-1 achieves brain penetration and bioavailability in normal CD-1 mice, and target engagement in 5xFAD mice. Chronic NVS-PAK1-1 treatment mitigates spine loss in the somatosensory cortex of 6-month-old 5xFAD female mice. Chronic treatment with NVS-PAK1-1 restores proteomic abundance of actin cytoskeleton and dendritic spine-associated proteins, including cofilin 2 and pyruvate dehydrogenase kinases, downstream of PAK1 in young 5xFAD female mice showing spine resilience. Clinical oncology trials with other PAK1 inhibitors support potential repurposing or novel compound development for Alzheimer's disease trials.
Authors
- Sean-Paul G. Williams (ORCID: https://orcid.org/0000-0002-5680-7730)
- Robert R. Butler (ORCID: https://orcid.org/0000-0003-0200-8682)
- Ranjita Betarbet (ORCID: https://orcid.org/0000-0002-4792-8952)
- Jacob L. Capener (ORCID: https://orcid.org/0000-0001-5051-2010)
- Frank M. Longo (ORCID: https://orcid.org/0000-0002-9514-7325)
- Carolyn Paisie (ORCID: https://orcid.org/0000-0003-4306-4154)
- Karina Leal
- Jesse C. Wiley (ORCID: https://orcid.org/0000-0002-1430-772X)
- Gregory A. Cary (ORCID: https://orcid.org/0000-0003-3573-5229)
- Hasi Huhe
- Yeonglong Albert Ay (ORCID: https://orcid.org/0009-0000-2255-3042)
- Jessica E. Young
- Haian Fu
- Drewry David
- T. Yang
- Sukhneet Kaur
- Zachary W. Davis‐Gilbert
- Mohammad A. Hossain
- Hans J. Oh
- Allan I. Levey
- Duc M Duong
- Gregory W. Carter
- Aled Edwards
- Nicholas T. Seyfried
- Stacey J. Sukoff Rizzo
Institutions
- University of North Carolina at Chapel Hill (US)
- Sage Bionetworks (US)
- Emory Healthcare (US)
- Emory University (US)
- University of Pittsburgh (US)
- University of Toronto (CA)
- Neurosciences Institute (US)
- Jackson Laboratory (US)
- UPMC Hillman Cancer Center (US)
- Stanford University (US)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1002/alz.71033
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Pharmaceutical Research and Manufacturers of America Foundation
- Pfizer
- Bayer
- University of Pittsburgh
- McGill University
- Genome Canada
- Jean Perkins Foundation
- Merck KGaA
- Ontario Genomics
- European Federation of Pharmaceutical Industries and Associations
- Applebaum Foundation
- Ontario Genomics Institute
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- National Institutes of Health
- Genentech
- National Institute on Aging