Department of Neurology, Saarland University, Homburg, Germany.
German Institute for Dementia Prevention (DIDP), Saarland University, Homburg, Germany.
Aging Cell. 2022 Aug;21(8):e13679. doi: 10.1111/acel.13679. Epub 2022 Jul 31.
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.
阿尔茨海默病（AD）是老年人中最常见的痴呆症病因，其病理特征为脑内细胞外沉积淀粉样β肽（Aβ）和小胶质细胞主导的炎症激活。p38α-MAPK 在神经元和小胶质细胞中均被激活。小胶质细胞中 p38α-MAPK 的激活如何促进 AD 的发病机制尚不清楚。在这项研究中，我们在 APP 转基因小鼠的所有髓系细胞或特异性地在小胶质细胞中条件性敲除了 p38α-MAPK，并在不同疾病阶段（例如，在 4 个月和 9 个月时）检查了动物的 AD 相关病理（即认知缺陷、Aβ 病理和神经炎症）和单个小胶质细胞的炎症激活和 Aβ 内化。我们的实验表明，与 p38α-MAPK 缺陷型小胶质细胞相比，p38α-MAPK 缺陷型髓系细胞更有效地减少 APP 转基因小鼠的大脑 Aβ 和神经元损伤。髓系细胞中 p38α-MAPK 的缺失抑制了 4 个月时单个小胶质细胞的炎症激活，但在 9 个月时增强了炎症激活。炎症激活促进了小胶质细胞对 Aβ 的内化。有趣的是，髓系细胞中 p38α-MAPK 的缺失减少了 9 个月而非 4 个月时 APP 转基因小鼠中表达 IL-17a 的 CD4 阳性淋巴细胞。通过将 APP 转基因小鼠与 Il-17a 敲除小鼠杂交，我们观察到 IL-17a 缺乏可潜在激活小胶质细胞并减少脑中的 Aβ 沉积，正如 9 个月时髓系 p38α-MAPK 缺陷型 AD 小鼠中所见。因此，所有髓系细胞而非仅小胶质细胞中的 p38α-MAPK 缺失可阻止 AD 的进展。表达 IL-17a 的淋巴细胞可能部分介导了 p38α-MAPK 在周围髓系细胞中的致病作用。我们的研究支持 p38α-MAPK 作为 AD 患者的治疗靶点。
