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J Neurosci. 2019 Aug 21;39(34):6766-6780. doi: 10.1523/JNEUROSCI.0884-19.2019. Epub 2019 Jun 19.

Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer's Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion.

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Departments of Neurobiology.
B.A. Neuroscience, and.
Statistics, The University of Chicago, Chicago, Illinois 60637.
Departments of Neurobiology,


Alzheimer's disease (AD) is a progressive neurodegenerative disorder that presently affects an estimated 5.7 million Americans. Understanding the basis for this disease is key for the development of a future successful treatment. In this effort, we previously reported that mouse prion protein-promoter-driven, ubiquitous expression of familial AD (FAD)-linked human PSEN1 variants in transgenic mice impairs environmental enrichment (EE)-induced proliferation and neurogenesis of adult hippocampal neural progenitor cells (AHNPCs) and in a non-cell autonomous manner. These findings were confirmed in PS1M146V/+ mice that harbor an FAD-linked mutation in the endogenous PSEN1 gene. We now demonstrate that CSF1R antagonist-mediated microglial depletion in transgenic male mice expressing mutant presenilin 1 (PS1) or PS1M146V/+ "knock-in" mice leads to a complete rescue of deficits in proliferation, differentiation and survival of AHNPCs. Moreover, microglia depletion suppressed the heightened baseline anxiety behavior observed in transgenic mice expressing mutant PS1 and PS1M146V/+ mice to levels observed in mice expressing wild-type human PS1 or nontransgenic mice, respectively. These findings demonstrate that in mice expressing FAD-linked PS1, microglia play a critical role in the regulation of EE-dependent AHNPC proliferation and neurogenesis and the modulation of affective behaviors.SIGNIFICANCE STATEMENT Inheritance of mutations in genes encoding presenilin 1 (PS1) causes familial Alzheimer's disease (FAD). Mutant PS1 expression enhances the levels and assembly of toxic Aβ42 peptides and impairs the self-renewal and neuronal differentiation of adult hippocampal neural progenitor cells (AHNPCs) following environmental enrichment (EE) that is associated with heightened baseline anxiety. We now show that microglial depletion fully restores the EE-mediated impairments in AHNPC phenotypes and suppresses the heightened baseline anxiety observed in mice expressing FAD-linked PS1. Thus, we conclude that the memory deficits and anxiety-related behaviors in patients with PS1 mutations is a reflection not just of an increase in the levels of Aβ42 peptides, but to impairments in the self-renewal and neuronal differentiation of AHNPCs that modulate affective behaviors.


Alzheimer; anxiety behaviors; environmental enrichment; hippocampal neurogenesis; microglia; presenilin

[Available on 2020-02-21]

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