論文 - 詳細
| RRC ID | 72380 |
|---|---|
| 著者 | Luo Q, Schnöder L, Hao W, Litzenburger K, Decker Y, Tomic I, Menger MD, Liu Y, Fassbender K. |
| タイトル | p38α-MAPK-deficient myeloid cells ameliorate symptoms and pathology of APP-transgenic Alzheimer's disease mice. |
| ジャーナル | Aging Cell |
| Abstract |
Alzheimer's disease (AD), the most common cause of dementia in the elderly, is pathologically characterized by extracellular deposition of amyloid-β peptides (Aβ) and microglia-dominated inflammatory activation in the brain. p38α-MAPK is activated in both neurons and microglia. How p38α-MAPK in microglia contributes to AD pathogenesis remains unclear. In this study, we conditionally knocked out p38α-MAPK in all myeloid cells or specifically in microglia of APP-transgenic mice, and examined animals for AD-associated pathologies (i.e., cognitive deficits, Aβ pathology, and neuroinflammation) and individual microglia for their inflammatory activation and Aβ internalization at different disease stages (e.g., at 4 and 9 months of age). Our experiments showed that p38α-MAPK-deficient myeloid cells were more effective than p38α-MAPK-deficient microglia in reducing cerebral Aβ and neuronal impairment in APP-transgenic mice. Deficiency of p38α-MAPK in myeloid cells inhibited inflammatory activation of individual microglia at 4 months but enhanced it at 9 months. Inflammatory activation promoted microglial internalization of Aβ. Interestingly, p38α-MAPK-deficient myeloid cells reduced IL-17a-expressing CD4-positive lymphocytes in 9 but not 4-month-old APP-transgenic mice. By cross-breeding APP-transgenic mice with Il-17a-knockout mice, we observed that IL-17a deficiency potentially activated microglia and reduced Aβ deposition in the brain as shown in 9-month-old myeloid p38α-MAPK-deficient AD mice. Thus, p38α-MAPK deficiency in all myeloid cells, but not only in microglia, prevents AD progression. IL-17a-expressing lymphocytes may partially mediate the pathogenic role of p38α-MAPK in peripheral myeloid cells. Our study supports p38α-MAPK as a therapeutic target for AD patients. |
| 巻・号 | 21(8) |
| ページ | e13679 |
| 公開日 | 2022-8-1 |
| DOI | 10.1111/acel.13679 |
| PMID | 35909315 |
| PMC | PMC9381888 |
| MeSH | Alzheimer Disease* / pathology Amyloid beta-Peptides / pharmacology Amyloid beta-Protein Precursor / genetics Animals Disease Models, Animal Interleukin-17 / pharmacology Mice Mice, Inbred C57BL Mice, Transgenic Microglia Mitogen-Activated Protein Kinase 14* / genetics Myeloid Cells |
| IF | 7.238 |
| 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 | News |
| 各媒体での言及数の合計 | 1 |
| 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 |