The Contributions of Microglial Vps35 to Adult Hippocampal Neurogenesis and Neurodegenerative Disorders

Abstract

The retromer complex is a multimeric protein complex which facilitates intracellular trafficking of a variety of transmembrane proteins. Vacuolar protein sorting-associated protein 35 (VPS35) is a critical component of retromer’s cargo recognition subunit and has been implicated in neurodegenerative disease pathology, including Alzheimer’s disease (AD). Without functional VPS35, trafficking of retromer cargo is often impaired, compromising cargo function and/or downstream signaling events. VPS35 expression is ubiquitous and can be found throughout the central nervous system (CNS). Microglia express VPS35, and microglia from AD patients exhibit reduced VPS35 expression. We sought to determine how microglial VPS35 loss-of-function might contribute to neurodegenerative disease pathology. We examined the CNS of a mouse model of heterozygous VPS35 deletion and found evidence suggesting upregulated microglial activity. To specifically examine the effects of microglial VPS35 loss-of-function, we developed VPS35CX3CR1 mice, a model which induces microglial-specific VPS35 depletion. Microglial VPS35 loss-of-function upregulated microglial density in a region-specific manner, which we determined to be an effect of increased microglial differentiation/survival. Upon further inspection, we found evidence of upregulated microglial inflammatory activity in the hippocampus, including increased levels of proinflammatory cytokine interleukin-6. Microglial density was increased within the subgranular zone (SGZ) of VPS35CX3CR1 mice, so we sought to determine if microglial VPS35 loss-of-function has any effect on hippocampal neurogenesis. While we found decreased doublecortin+ (DCX) immature neurons, an increase was observed in the differentiation/survival of neural progenitor cells (NPCs). Further analysis suggested the cell cycle exit of VPS35CX3CR1 hippocampal NPCs may be compromised. To examine morphology of newborn neurons, hippocampi were labeled with a retroviral vector, revealing impaired dendritic development in newborn hippocampal VPS35CX3CR1 neurons. Aberrant regulation of hippocampal neurogenesis in VPS35CX3CR1 mice was associated with a depressive behavioral phenotype and long-term memory impairment. These findings implicate a novel microglial-specific role of VPS35 that might contribute to neurodegenerative disease pathogenesis. The full extent of this role remains to be determined, as well as the mechanisms underlying our observations. It also remains to be determined what role microglial VPS35 might play in other brain regions, and how microglial VPS35 depletion might contribute to other aspects of neurodegenerative disease pathology.