Deficiency of p38&α-MAPK in myeloid cells ameliorates symptoms and pathology of APP-transgenic AD mice

Abstract

Microglial activation is a hall marker of Alzheimers disease (AD); its pathogenic role and regulating mechanisms are unclear. p38-MAPK, a stress-responding kinase, is activated in AD brain in early disease stages. In APP-transgenic mice, we deleted p38-MAPK in whole myeloid cells from birth or specifically in microglia from 9 months, and analysed AD pathology at the age of 4, 9 and 12 months. In both experimental settings, p38-MAPK deficiency decreased cerebral A{beta} and improved cognitive function of AD mice; however, p38-MAPK-deficient myeloid cells were more effective than p38-MAPK-deficient microglia in preventing AD pathogenesis. Deficiency of p38-MAPK in myeloid cells inhibited the inflammatory activation of individual microglia by 4 months, but enhanced it by 9 months. Inflammatory activation was essential for p38-MAPK deficiency to promote microglial internalization of A{beta}. Interestingly, p38-MAPK deficiency in peripheral myeloid cells reduced il-17a transcription in CD4-positive spleen cells. By cross-breeding APP-transgenic mice and IL-17a knockout mice, we further observed that IL-17a deficiency activated microglia and decreased A{beta} deposits in AD mouse brain. Thus, p38-MAPK deficiency in myeloid cells prevents AD pathogenesis, perhaps through reducing IL-17a-expressing T lymphocytes, and promoting A{beta} clearance in the brain. Our study supports p38-MAPK as a novel target for AD therapy.