論文 - 詳細
| 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC02192 |