| First Author | Schnöder L | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 5 | Pages | 2067-79 |
| PubMed ID | 26663083 | Mgi Jnum | J:259402 |
| Mgi Id | MGI:6147877 | Doi | 10.1074/jbc.M115.695916 |
| Citation | Schnoder L, et al. (2016) Deficiency of Neuronal p38alpha MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1. J Biol Chem 291(5):2067-79 |
| abstractText | Amyloid beta (Abeta) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in Abeta generation. Neuroinflammation potentially up-regulates BACE1 expression and increases Abeta 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 p38alpha MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38alpha MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated Abeta generation in the AD mouse brain. Inhibition of p38alpha MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38alpha MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38alpha MAPK plays a critical role in the regulation of BACE1 degradation and Abeta generation in AD pathogenesis. |
