Bio@SNS Laboratory, Scuola Normale Superiore, Piazza dei Cavalieri 7, Pisa, 56126, Italy.
European Brain Research Institute-Fondazione Rita Levi Montalcini, Viale Regina Elena 295, Roma, 00161, Italy.
Glia. 2018 Jul;66(7):1395-1416. doi: 10.1002/glia.23312. Epub 2018 Feb 23.
Microglia are the sentinels of the brain but a clear understanding of the factors that modulate their activation in physiological and pathological conditions is still lacking. Here we demonstrate that Nerve Growth Factor (NGF) acts on microglia by steering them toward a neuroprotective and anti-inflammatory phenotype. We show that microglial cells express functional NGF receptors in vitro and ex vivo. Our transcriptomic analysis reveals how, in primary microglia, NGF treatment leads to a modulation of motility, phagocytosis and degradation pathways. At the functional level, NGF induces an increase in membrane dynamics and macropinocytosis and, in vivo, it activates an outward rectifying current that appears to modulate glutamatergic neurotransmission in nearby neurons. Since microglia are supposed to be a major player in Aβ peptide clearance in the brain, we tested the effects of NGF on its phagocytosis. NGF was shown to promote TrkA-mediated engulfment of Aβ by microglia, and to enhance its degradation. Additionally, the proinflammatory activation induced by Aβ treatment is counteracted by the concomitant administration of NGF. Moreover, by acting specifically on microglia, NGF protects neurons from the Aβ-induced loss of dendritic spines and inhibition of long term potentiation. Finally, in an ex-vivo setup of acute brain slices, we observed a similar increase in Aβ engulfment by microglial cells under the influence of NGF. Our work substantiates a role for NGF in the regulation of microglial homeostatic activities and points toward this neurotrophin as a neuroprotective agent in Aβ accumulation pathologies, via its anti-inflammatory activity on microglia.
小胶质细胞是大脑的哨兵，但对于调节其在生理和病理条件下激活的因素，我们仍缺乏清晰的认识。在这里，我们证明神经生长因子（NGF）通过引导小胶质细胞向神经保护和抗炎表型来作用于小胶质细胞。我们表明，体外和离体培养的小胶质细胞表达功能性 NGF 受体。我们的转录组分析揭示了 NGF 处理如何导致原代小胶质细胞中运动性、吞噬作用和降解途径的调节。在功能水平上，NGF 诱导质膜动力学和巨胞饮作用的增加，并且在体内，它激活一种外向整流电流，似乎调节附近神经元中的谷氨酸能神经传递。由于小胶质细胞被认为是大脑中 Aβ 肽清除的主要参与者，我们测试了 NGF 对其吞噬作用的影响。NGF 被证明可促进小胶质细胞通过 TrkA 介导的 Aβ 吞噬作用，并增强其降解。此外，Aβ 处理诱导的促炎激活可被 NGF 的同时给药所拮抗。此外，通过特异性作用于小胶质细胞，NGF 可保护神经元免受 Aβ 诱导的树突棘丢失和长时程增强抑制。最后，在急性脑切片的离体设置中，我们观察到在 NGF 的影响下，小胶质细胞对 Aβ 的吞噬作用增加。我们的工作证实了 NGF 在小胶质细胞稳态活动调节中的作用，并指出这种神经营养因子通过其对小胶质细胞的抗炎活性，在 Aβ 积累病理中作为一种神经保护剂发挥作用。
