PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice.
| Title: | PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice. |
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| Authors: | Yang T; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.; Huhe H; Department of Medicine-Aging Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Williams SP; Department of Medicine-Aging Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Kaur S; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.; Ay YA; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.; Davis-Gilbert ZW; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Cary GA; The Jackson Laboratory, Bar Harbor, Maine, USA.; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA.; Paisie C; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.; Butler RR 3rd; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.; Wiley J; Sage Bionetworks, Seattle, Washington, USA.; Betarbet R; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA.; Department of Neurology, Emory University, Atlanta, Georgia, USA.; Fu H; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA.; Department of Pharmacology and Chemical Biology, Emory University, Atlanta, Georgia, USA.; Duong D; Emory Integrated Proteomics Core (EIPC), Emory University, Atlanta, Georgia, USA.; Seyfried NT; Emory Integrated Proteomics Core (EIPC), Emory University, Atlanta, Georgia, USA.; Department of Department of Biochemistry, Emory University, Atlanta, Georgia, USA.; Leal K; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA.; Sage Bionetworks, Seattle, Washington, USA.; Carter GW; The Jackson Laboratory, Bar Harbor, Maine, USA.; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA.; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.; Edwards A; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA.; Department of Medical Genetics and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.; Levey AI; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA.; Department of Neurology, Emory University, Atlanta, Georgia, USA.; Capener JL; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Drewry DH; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Hossain MA; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Oh HJ; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Axtman AD; Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA.; Sukoff Rizzo SJ; Department of Medicine-Aging Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA.; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Longo FM; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA.; Wu Tsai Neuroscience Institute, Stanford University, Stanford, California, USA. |
| Corporate Authors: | Emory‐Sage‐SGC‐Jax TREAT‐AD Center; The Emory-Sage-SGC-Jax TREAT-AD Center, Emory, USA. |
| Source: | Alzheimer's & dementia : the journal of the Alzheimer's Association [Alzheimers Dement] 2025 Dec; Vol. 21 (12), pp. e71033. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: John Wiley & Sons, Ltd Country of Publication: United States NLM ID: 101231978 Publication Model: Print Cited Medium: Internet ISSN: 1552-5279 (Electronic) Linking ISSN: 15525260 NLM ISO Abbreviation: Alzheimers Dement Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2020- : Hoboken, NJ : John Wiley & Sons, Ltd.; Original Publication: Orlando, FL : Elsevier, Inc. |
| MeSH Terms: | Dendritic Spines*/drug effects ; Dendritic Spines*/pathology ; Dendritic Spines*/metabolism ; p21-Activated Kinases*/antagonists & inhibitors ; p21-Activated Kinases*/metabolism ; tau Proteins*/metabolism ; Amyloid beta-Peptides*/metabolism ; Amyloid beta-Peptides*/toxicity ; Alzheimer Disease*/pathology ; Alzheimer Disease*/metabolism ; Alzheimer Disease*/drug therapy ; Neurons*/drug effects ; Neurons*/metabolism; Hippocampus/drug effects ; Hippocampus/pathology ; Animals ; Mice, Transgenic ; Disease Models, Animal ; Mice ; Female ; Humans ; Dibenzazepines ; Pyrrolidines |
| 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 (EC50 = 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.; (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.) |
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| Grant Information: | U54 AG065187 United States AG NIA NIH HHS; PhRMA Foundation; Archer Fund; Jean Perkins Foundation; NIH grants NIA U54AG065187; Applebaum Foundation Fund; The SGC is a registered charity that receives funds from Bayer AG, Boehringer Ingelheim |
| Contributed Indexing: | Keywords: Alzheimer's disease; NVS‐PAK1‐1; oligomeric amyloid beta; oligomeric tau; p21‐activated kinase 1; p21‐activated kinase 1 inhibitor; spine integrity |
| Substance Nomenclature: | EC 2.7.11.1 (p21-Activated Kinases); 0 (tau Proteins); 0 (Amyloid beta-Peptides); EC 2.7.11.1 (Pak1 protein, mouse); 0 (NVS-PAK1-1); 0 (Dibenzazepines); 0 (Pyrrolidines) |
| Entry Date(s): | Date Created: 20251226 Date Completed: 20251226 Latest Revision: 20260520 |
| Update Code: | 20260521 |
| PubMed Central ID: | PMC12741935 |
| DOI: | 10.1002/alz.71033 |
| PMID: | 41451871 |
| Database: | MEDLINE |
Journal Article