title: Targeting neuronal MAPK14/p38α activity to modulate autophagy in the Alzheimer disease brain.
abstract: Dysregulated autophagic-lysosomal degradation of proteins has been linked to the most common genetic defect in familial Alzheimer disease, and has been correlated with disease progression in both human disease and in animal models. Recently, it was demonstrated that the expression of MAPK14/p38α protein is upregulated in the brain of APP-PS1 transgenic Alzheimer mouse and further that genetic deficiency of Mapk14 in the APP-PS1 mouse stimulates macroautophagy/autophagy, which then leads to reduced amyloid pathology via increasing autophagic-lysosomal degradation of BACE1. The findings resolve at least in the context of the APP-PS1 mouse, prior conflicting in vitro observations that have implicated MAPK14 in autophagic processes, and indicate that inhibition of MAPK14 enzyme activity has potential as a therapeutic approach to mitigate a critical physiological defect within neurons of the Alzheimer disease brain. Moreover, the findings suggest that biomarkers of BACE1 activity could be utilized to evaluate the effects of MAPK14 inhibition and other autophagy-inducing therapeutic approaches in human clinical studies, thereby potentially facilitating the clinical development of such agents.
authors.affiliation: a EIP Pharma LLC , Cambridge , MA , USA.
authors.forename: John
authors.initials: J
authors.lastname: Alam
authors.affiliation: b Department of Functional Genomics , Center for Neurogenomics and Cognitive Research, VU University , Amsterdam , The Netherlands.|c Department of Clinical Genetics and Alzheimer Center , VU University Medical Center , Amsterdam , The Netherlands.
authors.forename: Wiep
authors.initials: W
authors.lastname: Scheper
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000201:enzymology* / Q000473:pathology*
chemical_list: D048308:Mitogen-Activated Protein Kinase 14
keywords: AKT; APP/PS1 mouse; Alzheimer disease; BACE1; MAPK14; MTOR; autophagy; biomarkers; p38α