| RRC ID |
36006
|
| Author |
Schnöder L, Hao W, Qin Y, Liu S, Tomic I, Liu X, Fassbender K, Liu Y.
|
| Title |
Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1.
|
| Journal |
J Biol Chem
|
| 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.
|
| Volume |
291(5)
|
| Pages |
2067-79
|
| Published |
2016-1-29
|
| DOI |
10.1074/jbc.M115.695916
|
| PII |
S0021-9258(20)36050-6
|
| PMID |
26663083
|
| PMC |
PMC4732195
|
| MeSH |
Alzheimer Disease / metabolism*
Amyloid / metabolism*
Amyloid Precursor Protein Secretases / metabolism*
Animals
Aspartic Acid Endopeptidases / metabolism*
Biological Transport
Brain / metabolism
Cell Line, Tumor
Disease Models, Animal
Genetic Vectors
Humans
Inflammation
Lysosomes / metabolism*
Mice
Mice, Transgenic
Mutation
Neurons / metabolism
Phosphorylation
Signal Transduction
p38 Mitogen-Activated Protein Kinases / metabolism*
|
| IF |
4.238
|
| Times Cited |
47
|
|
WOS Category
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| Resource |
| Mice |
RBRC02192 |
