Abstract
Microglial activation is a hall marker of Alzheimer’s disease (AD); its pathogenic role and regulating mechanisms are unclear. In APP-transgenic mice, we deleted p38α-MAPK in the myeloid cell lineage from birth or specifically in microglia from 9 months, and analysed the 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 deficiency in whole myeloid cells was more effective than specifically in microglia in preventing AD pathogenesis. Deficiency of p38α-MAPK in whole 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 in the brain. In the investigation of mechanisms mediating different effects of p38α-MAPK-deficient myeloid cells and p38α-MAPK-deficient microglia on the pathogenesis of AD mice, we observed that 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 found that IL-17a deficiency activated microglia and decreased Aβ deposits in AD mouse brain. In summary, our study shows that p38α-MAPK deficiency in myeloid cells attenuates symptoms and pathology of APP-transgenic mice. As a potential mechanism, p38α-MAPK-deficient peripheral myeloid cells reduces IL-17a-expressing T lymphocytes, and subsequently regulates cerebral Aβ clearance in APP-transgenic mice. Together with our previous observations that a deficiency of p38α-MAPK in neurons prevents AD pathogenesis, our study supports p38α-MAPK as a novel target for AD therapy.
Competing Interest Statement
The authors have declared no competing interest.