Microglia actively monitor the neighboring brain microenvironments and constantly contact synapses with their unique ramified processes. In neurodegenerative diseases, including Alzheimer’s disease (AD), microglia undergo morphological and functional alterations. Whether the direct manipulation of microglia can selectively or concurrently modulate synaptic function and the response to disease-associated factors remains elusive. Here, we employ optogenetic methods to stimulate microglia in vitro and in vivo. Membrane depolarization rapidly changes microglia morphology and leads to enhanced phagocytosis. We found that the optogenetic stimulation of microglia can efficiently promote β-amyloid (Aβ) clearance in the brain parenchyma, but it can also enhance synapse elimination. Importantly, the inhibition of C1q selectively prevents synapse loss induced by microglia depolarization but does not affect Aβ clearance. Our data reveal independent microglia-mediated phagocytosis pathways toward Aβ and synapses. Our results also shed light on a synergistic strategy of depolarizing microglia and inhibiting complement functions for the clearance of Aβ while sparing synapses.

小胶质细胞积极监测邻近的大脑微环境，并通过其独特的分支过程不断接触突触。在神经退行性疾病中，包括阿尔茨海默病 (AD)，小胶质细胞会发生形态和功能改变。直接操纵小胶质细胞是否可以选择性或​​同时调节突触功能以及对疾病相关因素的反应仍然难以捉摸。在这里，我们采用光遗传学方法在体外和体内刺激小胶质细胞。膜去极化迅速改变小胶质细胞的形态并导致吞噬作用增强。我们发现小胶质细胞的光遗传学刺激可以有效促进脑实质中β-淀粉样蛋白（Aβ）的清除，但它也可以增强突触的消除。重要的是，C1q 的抑制选择性地防止小胶质细胞去极化引起的突触损失，但不影响 Aβ 清除。我们的数据揭示了小胶质细胞介导的 Aβ 和突触的独立吞噬途径。我们的结果还揭示了去极化小胶质细胞和抑制补体功能以清除 Aβ 同时保护突触的协同策略。