| First Author | Schnöder L | Year | 2020 |
| Journal | FASEB J | Volume | 34 |
| Issue | 7 | Pages | 9628-9649 |
| PubMed ID | 32475008 | Mgi Jnum | J:303141 |
| Mgi Id | MGI:6511361 | Doi | 10.1096/fj.201902731RR |
| Citation | Schnoder L, et al. (2020) Neuronal deficiency of p38alpha-MAPK ameliorates symptoms and pathology of APP or Tau-transgenic Alzheimer's mouse models. FASEB J 34(7):9628-9649 |
| abstractText | Alzheimer's disease (AD) is the leading cause of dementia with very limited therapeutic options. Amyloid beta (Abeta) and phosphorylated Tau (p-Tau) are key pathogenic molecules in AD. P38alpha-MAPK is specifically activated in AD lesion sites. However, its effects on AD pathogenesis, especially on p-Tau-associated brain pathology, and the underlying molecular mechanisms remain unclear. We mated human APP-transgenic mice and human P301S Tau-transgenic mice with mapk14-floxed and neuron-specific Cre-knock-in mice. We observed that deletion of p38alpha-MAPK specifically in neurons improves the cognitive function of both 9-month-old APP and Tau-transgenic AD mice, which is associated with decreased Abeta and p-Tau load in the brain. We further used next-generation sequencing to analyze the gene transcription in brains of p38alpha-MAPK deficient and wild-type APP-transgenic mice, which indicated that deletion of p38alpha-MAPK regulates the transcription of calcium homeostasis-related genes, especially downregulates the expression of grin2a, a gene encoding NMDAR subunit NR2A. Cell culture experiments further verified that deletion of p38alpha-MAPK inhibits NMDA-triggered calcium influx and neuronal apoptosis. Our systemic studies of AD pathogenic mechanisms using both APP- and Tau-transgenic mice suggested that deletion of neuronal p38alpha-MAPK attenuates AD-associated brain pathology and protects neurons in AD pathogenesis. This study supports p38alpha-MAPK as a novel target for AD therapy. |
