Abstract
Neuroinflammation is a fundamental mechanism in Alzheimer's disease (AD) progression. The stress-induced activation of the p38α mitogen-activated protein kinase (MAPK) leads to increased production of proinflammatory cytokines and neurodegeneration. We investigated the effects of an isoform selective p38α MAPK inhibitor, MW01-18-150SRM (MW150), administered at 2.5 mg/kg/d (i.p.; 14 days) on early entorhinal cortex (EC) alterations in an AD mouse model carrying human mutations of the amyloid precursor protein (mhAPP). We used electrophysiological analyses with long-term potentiation induction in EC-containing brain slices and EC-relevant associative memory tasks. We found that MW150 was capable of rescuing long-term potentiation in 2-month old mhAPP mice. Acute delivery of MW150 to brain slices was similarly effective in rescuing long-term potentiation, with a comparable efficacy to that of the widely used multikinase inhibitor SB203580. MW150-treated mhAPP mice demonstrated improved ability to discriminate novel associations between objects and their position/context. Our findings suggest that the selective inhibition of the stress-activated p38α MAPK with MW150 can attenuate the EC dysfunctions associated with neuroinflammation in an early stage of AD progression.
Original language | English (US) |
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Pages (from-to) | 86-91 |
Number of pages | 6 |
Journal | Neurobiology of Aging |
Volume | 70 |
DOIs | |
State | Published - Oct 2018 |
Funding
Funding sources: This work was supported by the CNR Research Project on Aging (N.O.) and by the U01 AG043415 grant (D.M.W.).
Keywords
- Entorhinal cortex
- Long-term potentiation
- Neuroinflammation
- Novel object recognition
- p38α MAPK inhibitor
- β-amyloid
ASJC Scopus subject areas
- General Neuroscience
- Aging
- Clinical Neurology
- Developmental Biology
- Geriatrics and Gerontology