We show here that both SHIP1 and its paralog SHIP2 are expressed at the protein level in microglia. To examine whether targeting of SHIP paralogs might influence microglial physiology and function we tested the capacity of SHIP1-selective, SHIP2-selective and pan-SHIP1/2 inhibitors for their ability to impact microglia proliferation, lysosomal compartment size and phagocytic function. We find that highly potent pan-SHIP1/2 inhibitors can significantly increase lysosomal compartment size and phagocytosis of dead neurons and Aβ1-42 by microglia in vitro We show that one of the more potent and water-soluble pan-SHIP1/2 inhibitors, K161, can penetrate the blood-brain barrier and consistent with this K161 increases the capacity of CNS-resident microglia to phagocytose beta-amyloid and apoptotic neurons following systemic administration. These findings provide the first demonstration that small molecule modulation of microglia function in vivo is feasible and suggest the possibility that dual inhibition of the SHIP1 and 2 paralogs could provide a novel means to enhance basal microglial homeostatic functions for therapeutic purposes in Alzheimer's Disease, and possibly other dementias where increased microglial function could be beneficial.

中文翻译：

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Pan-SHIP1/2 抑制剂促进小胶质细胞效应器功能，这对于中枢神经系统稳态至关重要。

我们在此表明​​ SHIP1 及其旁系同源物 SHIP2 在小胶质细胞中以蛋白质水平表达。为了检查 SHIP 旁系同源物的靶向是否可能影响小胶质细胞的生理学和功能，我们测试了 SHIP1 选择性、SHIP2 选择性和泛 SHIP1/2 抑制剂影响小胶质细胞增殖、溶酶体区室大小和吞噬功能的能力。我们发现，高效的 p​​an-SHIP1/2 抑制剂可以在体外显着增加溶酶体区室的大小以及小胶质细胞对死亡神经元和 Aβ1-42 的吞噬作用。我们表明，K161 是一种更有效的水溶性泛 SHIP1/2 抑制剂，可以穿透血脑屏障，与此一致，K161 增加全身给药后中枢神经系统驻留小胶质细胞吞噬 β-淀粉样蛋白和凋亡神经元的能力。这些发现首次证明小分子调节体内小胶质细胞功能是可行的，并表明 SHIP1 和 2 旁系同源物的双重抑制可能提供一种新方法来增强基础小胶质细胞稳态功能，用于阿尔茨海默病的治疗目的，并且可能增加小胶质细胞功能可能有益的其他痴呆症。