Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan.
J Neuroinflammation. 2024 Oct 23;21(1):273. doi: 10.1186/s12974-024-03253-x.
Alzheimer's disease (AD) is a neurodegenerative disease that causes cognitive dysfunction in older adults. One of the AD pathological factors, β-Amyloid (Aβ), triggers inflammatory responses and phagocytosis of microglia. C-type lectin domain family 5 member A (CLEC5A) induces over-reactive inflammatory responses in several virus infections. Yet, the role of CLEC5A in AD progression remains unknown. This study aimed to elucidate the contribution of CLEC5A to Aβ-induced microglial activation and behavioral deficits.
The AD mouse model was crossed with Clec5a knockout mice for subsequent behavioral and pathological tests. The memory deficit was revealed by the Morris water maze, while the nociception abnormalities were examined by the von Frey filament and hotplate test. The Aβ deposition and microglia recruitment were identified by ELISA and immunohistochemistry. The inflammatory signals were identified by ELISA and western blotting. In the Clec5a knockdown microglial cell model and Clec5a knockout primary microglia, the microglial phagocytosis was revealed using the fluorescent-labeled Aβ.
The AD mice with Clec5a knockout improved Aβ-induced memory deficit and abnormal nociception. These mice have reduced Aβ deposition and increased microglia coverage surrounding the amyloid plaque, suggesting the involvement of CLEC5A in AD progression and Aβ clearance. Moreover, the phagocytosis was also increased in the Aβ-stressed Clec5a knockdown microglial cell lines and Clec5a knockout primary microglia.
The Clec5a knockout ameliorates AD-like deficits by modulating microglial Aβ clearance. This study implies that targeting microglial Clec5a could offer a promising approach to mitigate AD progression.
阿尔茨海默病（AD）是一种神经退行性疾病，可导致老年人认知功能障碍。AD 的病理因素之一β-淀粉样蛋白（Aβ）会引发小胶质细胞的炎症反应和吞噬作用。C 型凝集素结构域家族 5 成员 A（CLEC5A）可在几种病毒感染中引发过度活跃的炎症反应。然而，CLEC5A 在 AD 进展中的作用尚不清楚。本研究旨在阐明 CLEC5A 对 Aβ诱导的小胶质细胞激活和行为缺陷的作用。
将 AD 小鼠模型与 Clec5a 基因敲除小鼠杂交，进行后续的行为和病理测试。通过 Morris 水迷宫揭示记忆缺陷，通过 von Frey 纤维和热板试验检测痛觉异常。通过 ELISA 和免疫组织化学检测 Aβ 沉积和小胶质细胞募集。通过 ELISA 和 Western blot 检测炎症信号。在 Clec5a 敲低小胶质细胞模型和 Clec5a 基因敲除原代小胶质细胞中，通过荧光标记的 Aβ 揭示小胶质细胞吞噬作用。
具有 Clec5a 基因敲除的 AD 小鼠改善了 Aβ 诱导的记忆缺陷和异常痛觉。这些小鼠的 Aβ 沉积减少，淀粉样斑块周围的小胶质细胞覆盖增加，表明 CLEC5A 参与 AD 进展和 Aβ 清除。此外，在 Aβ 应激的 Clec5a 敲低小胶质细胞系和 Clec5a 基因敲除原代小胶质细胞中，吞噬作用也增加。
Clec5a 基因敲除通过调节小胶质细胞 Aβ 清除来改善 AD 样缺陷。本研究表明，靶向小胶质细胞 CLEC5A 可能是减轻 AD 进展的一种有前途的方法。
