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A small molecule p38α MAPK inhibitor, MW150, attenuates behavioral deficits and neuronal dysfunction in a mouse model
Hilaree N Frazier1, David J Braun1,2, Caleb S Bailey1
1Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA.
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.
Insights
Inhibiting p38 alpha kinase (p38α) improved cognition in Alzheimer's disease models with mixed pathologies. The drug MW150 rescued neuronal function without affecting amyloid or vascular damage, suggesting a potential therapy for cognitive preservation.
Area of Science:
- Neuroscience
- Pharmacology
- Alzheimer's Disease Research
Background:
- Alzheimer's disease (AD) often co-occurs with vascular pathologies, complicating treatment.
- Previous studies on p38 alpha mitogen activated protein kinase (p38α) inhibitors used pure AD models.
- This study investigates p38α inhibition in a mixed AD and vascular pathology model.
Purpose of the Study:
- To evaluate the efficacy of p38α inhibition in a mouse model with comorbid amyloid and vascular pathologies.
- To determine if p38α inhibition can ameliorate cognitive dysfunction in a mixed pathology setting.
Main Methods:
- Used 5xFAD mice, a model for amyloid pathology.
- Induced small vessel disease via a hyperhomocysteinemia diet.
- Treated mice with the p38α inhibitor MW150 during the diet.
- Assessed cognitive function, synaptic integrity, tau phosphorylation, and electrophysiology.
Main Results:
- MW150 treatment improved behavioral performance in the Morris Water Maze.
- Synaptic loss was attenuated, and tau phosphorylation was reduced.
- Electrophysiological parameters showed partial normalization.
- No significant effects were observed on amyloid burden, vascular pathology, or neuroinflammation.
Conclusions:
- p38α inhibition offers cognitive benefits even with mixed pathologies.
- The therapeutic effect is primarily through rescuing neuronal function, not by altering primary pathologies.
- p38α inhibitors may be valuable for preserving cognition in AD, alone or with other therapies.
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