Increased microglial activity, impaired adult hippocampal neurogenesis, and depressive-like behavior in microglial VPS35-depleted mice

Joanna Ruth Appel, Shiyang Ye, Fulei Tang, Dong Sun, Hongsheng Zhang, Lin Mei, Wen Cheng Xiong

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5949-5968
Number of pages20
JournalJournal of Neuroscience
Volume38
Issue number26
DOIs
StatePublished - Jun 27 2018

Fingerprint

Neurogenesis
Microglia
Dentate Gyrus
Dendritic Spines
Alzheimer Disease
Brain
Neurons
Parahippocampal Gyrus
Long-Term Memory
Endosomes
Protein Transport
Neurodegenerative Diseases
Membrane Proteins
Depression
Pathology
Phenotype

Keywords

  • Alzheimer’s disease
  • Hippocampus
  • Microglia
  • Neurogenesis
  • Retromer
  • VPS35

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Increased microglial activity, impaired adult hippocampal neurogenesis, and depressive-like behavior in microglial VPS35-depleted mice. / Appel, Joanna Ruth; Ye, Shiyang; Tang, Fulei; Sun, Dong; Zhang, Hongsheng; Mei, Lin; Xiong, Wen Cheng.

In: Journal of Neuroscience, Vol. 38, No. 26, 27.06.2018, p. 5949-5968.

Research output: Contribution to journalArticle

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abstract = "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.",
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