Document Type
Article
Publication Date
12-1-2025
Original Citation
Yang T,
Huhe H,
Williams S,
Kaur S,
Ay Y,
Davis-Gilbert Z,
Cary G,
Paisie C,
Butler R,
Wiley J,
Betarbet R,
Fu H,
Duong D,
Seyfried N,
Leal K,
Carter GW,
Edwards A,
Levey A,
Capener J,
Drewry D,
Hossain M,
Oh H,
Axtman A,
Sukoff Rizzo S,
Longo F,
.
PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice. Alzheimers Dement. 2025;21(12):e71033.
Keywords
JGM, JMG, Animals, Dendritic Spines, p21-Activated Kinases, tau Proteins, Amyloid beta-Peptides, Mice, Transgenic, Alzheimer Disease, Neurons, Hippocampus, Disease Models, Animal, Mice, Female, Humans, Dibenzazepines, Pyrrolidines
JAX Source
Alzheimers Dement. 2025;21(12):e71033.
ISSN
1552-5279
PMID
41451871
DOI
https://doi.org/10.1002/alz.71033
Grant
This work was sup- ported in part by NIH grants NIA U54AG065187 (TREAT-AD, Allan I. Levey, Gregory W. Carter, Aled Edwards, Haian Fu, Frank M. Longo, Alison D. Axtman)
Abstract
INTRODUCTION: Synaptic spine loss in Alzheimer's disease (AD) contributes to cognitive decline. p21-activated kinase 1 (PAK1), a regulator of spine integrity, is aberrantly activated in AD. We investigated whether PAK1 inhibition might preserve dendritic spines in vitro and in vivo.
METHODS: Oligomeric amyloid beta (oAβ) or tau (oTau) were applied to hippocampal neurons ± NVS-PAK1-1, a selective PAK1 inhibitor. NVS-PAK1-1 was orally administered to 5xFAD mice. The effects of NVS-PAK1-1 treatment on PAK1 activity, spine density, and the proteome were assessed using phospho-PAK1 (pPAK1) western blotting, Golgi staining, and mass spectrometry for proteomic analyses.
RESULTS: NVS-PAK1-1 prevented oAβ and oTau-induced spine loss in vitro. In 5xFAD mice, NVS-PAK1-1 demonstrated brain exposure after oral administration and reduced PAK1 activation, prevented spine loss, and partially normalized synaptic proteomic signatures in females in absence of alterations in brain or plasma Aβ.
DISCUSSION: PAK1 inhibition enhances spine resilience in AD models, supporting its therapeutic potential.
HIGHLIGHTS: 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
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.