RRC ID 72380
Author Luo Q, Schnöder L, Hao W, Litzenburger K, Decker Y, Tomic I, Menger MD, Liu Y, Fassbender K.
Title p38α-MAPK-deficient myeloid cells ameliorate symptoms and pathology of APP-transgenic Alzheimer's disease mice.
Journal Aging Cell
Abstract Alzheimer's disease (AD), the most common cause of dementia in the elderly, is pathologically characterized by extracellular deposition of amyloid-β peptides (Aβ) and microglia-dominated inflammatory activation in the brain. p38α-MAPK is activated in both neurons and microglia. How p38α-MAPK in microglia contributes to AD pathogenesis remains unclear. In this study, we conditionally knocked out p38α-MAPK in all myeloid cells or specifically in microglia of APP-transgenic mice, and examined animals for AD-associated pathologies (i.e., cognitive deficits, Aβ pathology, and neuroinflammation) and individual microglia for their inflammatory activation and Aβ internalization at different disease stages (e.g., at 4 and 9 months of age). Our experiments showed that p38α-MAPK-deficient myeloid cells were more effective than p38α-MAPK-deficient microglia in reducing cerebral Aβ and neuronal impairment in APP-transgenic mice. Deficiency of p38α-MAPK in myeloid cells inhibited inflammatory activation of individual microglia at 4 months but enhanced it at 9 months. Inflammatory activation promoted microglial internalization of Aβ. Interestingly, p38α-MAPK-deficient myeloid cells reduced IL-17a-expressing CD4-positive lymphocytes in 9 but not 4-month-old APP-transgenic mice. By cross-breeding APP-transgenic mice with Il-17a-knockout mice, we observed that IL-17a deficiency potentially activated microglia and reduced Aβ deposition in the brain as shown in 9-month-old myeloid p38α-MAPK-deficient AD mice. Thus, p38α-MAPK deficiency in all myeloid cells, but not only in microglia, prevents AD progression. IL-17a-expressing lymphocytes may partially mediate the pathogenic role of p38α-MAPK in peripheral myeloid cells. Our study supports p38α-MAPK as a therapeutic target for AD patients.
Volume 21(8)
Pages e13679
Published 2022-8-1
DOI 10.1111/acel.13679
PMID 35909315
PMC PMC9381888
MeSH Alzheimer Disease* / pathology Amyloid beta-Peptides / pharmacology Amyloid beta-Protein Precursor / genetics Animals Disease Models, Animal Interleukin-17 / pharmacology Mice Mice, Inbred C57BL Mice, Transgenic Microglia Mitogen-Activated Protein Kinase 14* / genetics Myeloid Cells
IF 7.238
Mice RBRC02192