P38α‐MAPK phosphorylates Snapin and reduces Snapin‐mediated BACE1 transportation in APP‐transgenic mice

Amyloid β peptide (Aβ) is the major pathogenic molecule in Alzheimer's disease (AD). BACE1 enzyme essential for generation of Aβ. Deficiency p38α-MAPK neurons increases lysosomal degradation and decreases Aβ deposition brain APP-transgenic mice. However, mechanisms mediating effects are largely unknown. In this study, we used mice cultured observed that deletion specifically decreased phosphorylation Snapin at serine, increased retrograde transportation axons reduced synaptic terminals, which suggests deficiency promotes axonal from its predominant locations, to lysosomes cell body. vitro kinase assay revealed directly phosphorylates Snapin. By further performing mass spectrometry analysis site-directed mutagenic experiments SH-SY5Y lines, identified serine residue 112 as a p38α-MAPK-phosphorylating site on Replacement with alanine did abolish knockdown-induced reduction activity protein level, cells. Taken together, our study activation inhibits axons, might exaggerate amyloid pathology AD brain.