| RRC ID |
60834
|
| 著者 |
Schnöder L, Gasparoni G, Nordström K, Schottek A, Tomic I, Christmann A, Schäfer KH, Menger MD, Walter J, Fassbender K, Liu Y.
|
| タイトル |
Neuronal deficiency of p38α-MAPK ameliorates symptoms and pathology of APP or Tau-transgenic Alzheimer's mouse models.
|
| ジャーナル |
FASEB J
|
| Abstract |
Alzheimer's disease (AD) is the leading cause of dementia with very limited therapeutic options. Amyloid β (Aβ) and phosphorylated Tau (p-Tau) are key pathogenic molecules in AD. P38α-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 p38α-MAPK specifically in neurons improves the cognitive function of both 9-month-old APP and Tau-transgenic AD mice, which is associated with decreased Aβ and p-Tau load in the brain. We further used next-generation sequencing to analyze the gene transcription in brains of p38α-MAPK deficient and wild-type APP-transgenic mice, which indicated that deletion of p38α-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 p38α-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 p38α-MAPK attenuates AD-associated brain pathology and protects neurons in AD pathogenesis. This study supports p38α-MAPK as a novel target for AD therapy.
|
| 巻・号 |
34(7)
|
| ページ |
9628-9649
|
| 公開日 |
2020-7-1
|
| DOI |
10.1096/fj.201902731RR
|
| PMID |
32475008
|
| MeSH |
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Alzheimer Disease / prevention & control*
Animals
Cognition Disorders / metabolism
Cognition Disorders / pathology
Cognition Disorders / prevention & control*
Disease Models, Animal*
Female
Inflammation / metabolism
Inflammation / pathology
Inflammation / prevention & control*
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitogen-Activated Protein Kinase 14 / deficiency*
Neurons / metabolism*
Phosphorylation
tau Proteins / genetics
tau Proteins / metabolism*
|
| IF |
5.391
|
| 引用数 |
1
|
| リソース情報 |
| 実験動物マウス |
RBRC02192 |
