title: Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.
abstract: Amyloid β (Aβ) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in Aβ generation. Neuroinflammation potentially up-regulates BACE1 expression and increases Aβ production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38α MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38α MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated Aβ generation in the AD mouse brain. Inhibition of p38α MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38α MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38α MAPK plays a critical role in the regulation of BACE1 degradation and Aβ generation in AD pathogenesis.
authors.affiliation: From the Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany, the German Institute for Dementia Prevention (DIDP), Saarland University, 66421 Homburg/Saar, Germany, and.
authors.forename: Laura
authors.initials: L
authors.lastname: Schnöder
authors.affiliation: From the Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany, the German Institute for Dementia Prevention (DIDP), Saarland University, 66421 Homburg/Saar, Germany, and.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Hao
authors.affiliation: From the Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany, the German Institute for Dementia Prevention (DIDP), Saarland University, 66421 Homburg/Saar, Germany, and.
authors.forename: Yiren
authors.initials: Y
authors.lastname: Qin
authors.affiliation: the Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115.
authors.forename: Shirong
authors.initials: S
authors.lastname: Liu
authors.affiliation: From the Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany, the German Institute for Dementia Prevention (DIDP), Saarland University, 66421 Homburg/Saar, Germany, and.
authors.forename: Inge
authors.initials: I
authors.lastname: Tomic
authors.affiliation: From the Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany, the German Institute for Dementia Prevention (DIDP), Saarland University, 66421 Homburg/Saar, Germany, and.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany, the German Institute for Dementia Prevention (DIDP), Saarland University, 66421 Homburg/Saar, Germany, and.
authors.forename: Klaus
authors.initials: K
authors.lastname: Fassbender
authors.affiliation: From the Department of Neurology, Saarland University, 66421 Homburg/Saar, Germany, the German Institute for Dementia Prevention (DIDP), Saarland University, 66421 Homburg/Saar, Germany, and a.liu@mx.uni-saarland.de.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005822:Genetic Vectors; D006801:Humans; D007249:Inflammation; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000682:Amyloid; D048051:p38 Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse
keywords: Alzheimer disease; amyloid-β (Aβ); autophagy; lysosome; p38 MAPK; β-secretase 1 (BACE1)