A small molecule p38α MAPK inhibitor, MW150, attenuates behavioral deficits and neuronal dysfunction in a mouse model of mixed amyloid and vascular pathologies.

Autor:	Frazier HN; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA., Braun DJ; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA.; Department of Neuroscience, University of Kentucky, Lexington, KY, 40536, USA., Bailey CS; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA., Coleman MJ; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA., Davis VA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA., Dundon SR; Magnetic Resonance Imaging & Spectroscopy Center, University of Kentucky, Lexington, KY, 40536, USA., McLouth CJ; Department of Biostatistics, University of Kentucky, Lexington, KY, 40536, USA., Muzyk HC; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA., Powell DK; Department of Neuroscience, University of Kentucky, Lexington, KY, 40536, USA.; Magnetic Resonance Imaging & Spectroscopy Center, University of Kentucky, Lexington, KY, 40536, USA., Rogers CB; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA., Roy SM; Department of Pharmacology, Northwestern University, Chicago, IL, 60611, USA., Van Eldik LJ; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA.; Department of Neuroscience, University of Kentucky, Lexington, KY, 40536, USA.
Jazyk:	angličtina
Zdroj:	Brain, behavior, & immunity - health [Brain Behav Immun Health] 2024 Jul 23; Vol. 40, pp. 100826. Date of Electronic Publication: 2024 Jul 23 (Print Publication: 2024).
DOI:	10.1016/j.bbih.2024.100826
Abstrakt:	Background: Inhibition of p38 alpha mitogen activated protein kinase (p38α) has shown great promise as a treatment for Alzheimer's disease (AD) in preclinical tests. However, previous preclinical studies were performed in "pure" models of AD pathology. A vast majority of AD patients have comorbid dementia-contributing pathologies, particularly some form of vascular damage. The present study therefore aimed to test the potential of p38α inhibition to address dysfunction in the context of comorbid amyloid and vascular pathologies. Methods: An amyloid overexpressing mouse strain (5xFAD) was placed on an 8-week long diet to induce the hyperhomocysteinemia (HHcy) model of small vessel disease. Mice were treated with the brain-penetrant small molecule p38α inhibitor MW150 for the duration of the HHcy diet, and subsequently underwent behavioral, neuroimaging, electrophysiological, or biochemical/immunohistochemical analyses. Results: MW150 successfully reduced behavioral impairment in the Morris Water Maze, corresponding with attenuation of synaptic loss, reduction in tau phosphorylation, and a partial normalization of electrophysiological parameters. No effect of MW150 was observed on the amyloid, vascular, or neuroinflammatory endpoints measured. Conclusions: This study provides proof-of-principle that the inhibition of p38α is able to provide benefit even in the context of mixed pathological contributions to cognitive impairment. Interestingly, the benefit was mediated primarily via rescue of neuronal function without any direct effects on the primary pathologies. These data suggest a potential use for p38 inhibitors in the preservation of cognition across contexts, and in particular AD, either alone or as an adjunct to other AD therapies ( i.e. anti-amyloid approaches). Future studies to delineate the precise neuronal pathways implicated in the benefit may help define other specific comorbid conditions amenable to this type of approach or suggest future refinement in pharmacological targeting. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2024 The Authors.)
Databáze:	MEDLINE
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