Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia 30912.
Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, and.
J Neurosci. 2018 Jun 27;38(26):5949-5968. doi: 10.1523/JNEUROSCI.3621-17.2018. Epub 2018 May 31.
Vacuolar sorting protein 35 (VPS35) is a critical component of retromer, which is essential for selective endosome-to-Golgi retrieval of membrane proteins. VPS35 deficiency is implicated in neurodegenerative disease pathology, including Alzheimer's disease (AD). However, exactly how VPS35 loss promotes AD pathogenesis remains largely unclear. VPS35 is expressed in various types of cells in the brain, including neurons and microglia. Whereas neuronal VPS35 plays a critical role in preventing neurodegeneration, the role of microglial VPS35 is largely unknown. Here we provide evidence for microglial VPS35's function in preventing microglial activation and promoting adult hippocampal neurogenesis. VPS35 is expressed in microglia in various regions of the mouse brain, with a unique distribution pattern in a brain region-dependent manner. Conditional knocking out of VPS35 in microglia of male mice results in regionally increased microglial density and activity in the subgranular zone of the hippocampal dentate gyrus (DG), accompanied by elevated neural progenitor proliferation, but decreased neuronal differentiation. Additionally, newborn neurons in the mutant DG show impaired dendritic morphology and reduced dendritic spine density. When examining the behavioral phenotypes of these animals, microglial VPS3S-depleted mice display depression-like behavior and impairment in long-term recognition memory. At the cellular level, VPS35-depleted microglia have grossly enlarged vacuolar structures with increased phagocytic activity toward postsynaptic marker PSD95, which may underlie the loss of dendritic spines observed in the mutant DG. Together, these findings identify an important role of microglial VPS35 in suppressing microglial activation and promoting hippocampal neurogenesis, which are both processes involved in AD pathogenesis. The findings presented here provide the first evidence that Vacuolar sorting protein 35 (VPS35)/retromer is essential for regulating microglial function and that when microglial retromer mechanics are disrupted, the surrounding brain tissue can be affected in a neurodegenerative manner. These findings present a novel, microglial-specific role of VPS35 and raise multiple questions regarding the mechanisms underlying our observations. These findings also have myriad implications for the field of retromer research and the role of retromer dysfunction in neurodegenerative pathophysiology. Furthermore, they implicate a pivotal role of microglia in the regulation of adult hippocampal neurogenesis and the survival/integration of newborn neurons in the adult hippocampus.
液泡分选蛋白 35（VPS35）是内体分选复合物-3（retromer）的关键组成部分，对膜蛋白的选择性内体-高尔基体回运至关重要。VPS35 缺失与神经退行性疾病病理有关，包括阿尔茨海默病（AD）。然而，VPS35 缺失如何促进 AD 发病机制仍不清楚。VPS35 在大脑中的多种类型细胞中表达，包括神经元和小胶质细胞。神经元中的 VPS35 对于预防神经退行性变起着至关重要的作用，而小胶质细胞中的 VPS35 的作用在很大程度上尚不清楚。在这里，我们提供了小胶质细胞中 VPS35 防止小胶质细胞激活和促进成年海马神经发生的功能的证据。VPS35 在各种脑区的小胶质细胞中表达，其分布模式具有脑区依赖性。在雄性小鼠的小胶质细胞中条件性敲除 VPS35 会导致海马齿状回（DG）颗粒下层的小胶质细胞密度和活性区域性增加，伴随着神经祖细胞增殖增加，但神经元分化减少。此外，突变 DG 中的新生神经元表现出受损的树突形态和减少的树突棘密度。当检查这些动物的行为表型时，小胶质细胞 VPS3S 耗竭的小鼠表现出抑郁样行为和长期识别记忆障碍。在细胞水平上，耗尽 VPS35 的小胶质细胞具有明显增大的空泡结构，对突触后标志物 PSD95 的吞噬活性增加，这可能是突变 DG 中观察到的树突棘丢失的基础。总之，这些发现确定了小胶质细胞 VPS35 在抑制小胶质细胞激活和促进海马神经发生中的重要作用，这两个过程都涉及 AD 的发病机制。本研究首次提供了证据表明液泡分选蛋白 35（VPS35）/retromer 对于调节小胶质细胞功能是必需的，当小胶质细胞 retromer 力学被破坏时，周围的脑组织可能以神经退行性方式受到影响。这些发现提出了 VPS35 的一种新的、小胶质细胞特异性作用，并提出了许多关于我们观察结果背后的机制的问题。这些发现还对 retromer 研究领域和 retromer 功能障碍在神经退行性病理生理学中的作用具有重要意义。此外，它们表明小胶质细胞在调节成年海马神经发生和成年海马中新神经元的存活/整合中起着关键作用。
