Early loss of microglial p38α MAPK in the APPswe/PS1dE9 mouse model of Alzheimer’s disease alters soluble amyloid beta and reduces microglia co‐localization with amyloid plaques without affecting amyloid‐associated pathology

Abstract

AbstractBackgroundThe p38 alpha mitogen‐activated protein kinase (p38α) pathway is linked to both innate and adaptive immune responses, and is currently under investigation as a target for drug development in the context of Alzheimer’s disease (AD) and other conditions with neuroinflammatory dysfunction (Asih et al., 2020). Preclinical data indicates that p38α inhibition can protect against AD‐associated neuropathology, although the cellular mechanisms and signaling pathways that underlie these effects have not been fully elucidated. Evidence suggests that inhibition of p38α may provide benefit by modulating microglial‐associated neuroinflammatory processes that contribute to the development of AD pathology. The present study tests this hypothesis by assessing early‐stage pathological changes in AD model mice following microglial‐specific knock out (KO) of p38α.MethodsKO of p38α in microglia was accomplished in 5‐month‐old C57BL/6J wild‐type and amyloidogenic AD model (APPswe/PS1dE9) mice using a tamoxifen‐inducible Cre/loxP system under control of the Cx3Cr1 promoter. Animals underwent behavioral assessment on the open field test at 7.5 months of age and on the radial arm water maze test at 11 months of age, followed by collection of cortical and hippocampal tissues. Other endpoint measures included quantification of proinflammatory cytokines, assessment of amyloid burden and plaque deposition, and characterization of microglia‐plaque dynamics using a combination of ELISA, immunohistochemical, and immunofluorescent techniques.ResultsSuppression of microglial p38α did not alter behavioral outcomes, proinflammatory cytokine levels, or overall amyloid plaque burden, but did significantly increase hippocampal levels of soluble Aβ42 and reduced hippocampal colocalization of Iba1 and 6E10 in a subset of microglia in close proximity to plaques.ConclusionThis work suggests that rather than reducing inflammation per se, microglial p38α inhibition in the context of early AD‐type amyloid pathology may alter hippocampal microglia‐plaque interactions. Additionally, these results support future investigations of microglial p38α signaling at different stages of disease, as well as the potential relationship between p38α and phagocytic processes in this particular cell‐type. Funding: This work is supported by the National Institutes of Health (RF1 AG064859; F32 AG058456; T32 AG057461).