p38α-MAPK-deficient myeloid cells ameliorate symptoms and pathology of APP-transgenic AD mice

Microglial activation is a hall marker of Alzheimer disease (AD); its pathogenic role and regulating mechanisms are unclear. p38α-MAPK, a stress-responding kinase, is activated in AD brain in early disease stages. In APP-transgenic mice, we deleted p38α-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, p38α-MAPK deficiency decreased cerebral Aβ and improved cognitive function in AD mice; however, p38α-MAPK-deficient myeloid cells were more effective than p38α-MAPK-deficient microglia in preventing AD pathogenesis. Deficiency of p38α-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 p38α-MAPK deficiency to promote microglial internalization of Aβ. Interestingly, p38α-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 Aβ deposits in AD mouse brain. Thus, p38α-MAPK deficiency in myeloid cells prevents AD pathogenesis, perhaps through reducing IL-17a-expressing T lymphocytes, and promoting Aβ clearance in the brain. Our study supports p38α-MAPK as a novel target for AD therapy.