Enrichment-dependent deficits in Hippocampal Neurogenesis mediated by familial Alzheimers disease-linked PS1 variants are rescued by microglial depletion

<p>Sylvia Ortega-Martinez, Nisha Palla, Xiaoqiong Zhang, Jonathan Foldi and Sangram S Sisodia</p>

Enrichment-dependent deficits in Hippocampal Neurogenesis mediated by familial Alzheimers disease-linked PS1 variants are rescued by microglial depletion

Sylvia Ortega-Martinez, Nisha Palla, Xiaoqiong Zhang, Jonathan Foldi and Sangram S Sisodia

The University of Chicago, USA

: J Addict Behav Ther Rehabil

Abstract

Presenilin 1 (PS1) plays a critical role in neurogenesis. We have demonstrated that ubiquitous expression of familial, early-onset Alzheimer’s disease (AD)-linked PS1 (FAD-PS1) mutants impairs environmental enrichment (EE)-induced proliferation and neurogenesis of adult hippocampal progenitor cells (AHNPCs) in a non-cell autonomous manner. These impairments are, at least in part, due to alterations in the levels of specific chemokines and growth factors secreted from microglia expressing FADPS1 variants. Mice expressing PrP promoter-driven human wild-type PS1, M146L and Ã¯ÂÂ„E9 were fed with PLX5562 for 7 days, then subject to Standard Housing or EE conditions for 1 month. PLX5622 is a CSF1 receptor antagonist, used to deplete microglia in adult brain. Animals were injected with a single bolus of BrdU, and sacrificed after 24 hours or 2 weeks. Baseline anxiety behavior was tested using Marble Burying and Dark/light test. Brain immunostaining was used to assess proliferation, neurogenic cell density, differentiation and survival of hippocampal progenitors. It was compared with mice expressing human WT PS1, mice expressing FAD-PS1 linked mutations exhibit lower rates of proliferation, neural stem cells and GFAP+ cells in the hippocampus following EE. These deficits were correlated with higher rates of baseline anxiety behaviors. PLX5622- mediated depletion of microglia in mice expressing FAD-PS1 linked variants rescued the deficits in AHNPC proliferation and differentiation and aberrant baseline anxiety. PLX5622- mediated depletion of microglia in mice expressing FAD-PS1 linked variants rescues deficits in AHNPC proliferation and baseline anxiety of those mice. These findings reinforce the important role of microglia in the regulation of neurogenesis in FAD-PS1 models.