Abstract
BackgroundAlzheimer’s disease (AD) is characterized by progressive memory loss and impaired cognitive function. Early-onset familial forms of the disease (FAD) are caused by inheritance of mutant genes encoding presenilin 1 (PS1) variants. We have demonstrated that prion promoter (PrP)-driven expression of human FAD-linked PS1 variants in mice leads to impairments in environmental enrichment (EE)-induced adult hippocampal neural progenitor cell (AHNPC) proliferation and neuronal differentiation, and have provided evidence that accessory cells in the hippocampal niche expressing PS1 variants may modulate AHNPC phenotypes, in vivo. While of significant interest, these latter studies relied on transgenic mice that express human PS1 variant transgenes ubiquitously and at high levels, and the consequences of wild type or mutant PS1 expressed under physiologically relevant levels on EE-mediated AHNPC phenotypes has not yet been tested.ResultsTo assess the impact of mutant PS1 on EE-induced AHNPC phenotypes when expressed under physiological levels, we exposed adult mice that constitutively express the PSEN1 M146V mutation driven by the endogenous PSEN1 promoter (PS1 M146V “knock-in” (KI) mice) to standard or EE-housed conditions. We show that in comparison to wild type PS1 mice, AHNPCs in mice carrying homozygous (PS1M146V/M146V) or heterozygous (PS1M146V/+) M146V mutant alleles fail to exhibit EE-induced proliferation and commitment towards neurogenic lineages. More importantly, we report that the survival of newborn progenitors are diminished in PS1 M146V KI mice exposed to EE-conditions compared to respective EE wild type controls.ConclusionsOur findings reveal that expression at physiological levels achieved by a single PS1 M146V allele is sufficient to impair EE-induced AHNPC proliferation, survival and neuronal differentiation, in vivo. These results and our finding that microglia expressing a single PS1 M146V allele impairs the proliferation of wild type AHNPCs in vitro argue that expression of mutant PS1 in the AHNPC niche impairs AHNPCs phenotypes in a dominant, non-cell autonomous manner.
Highlights
Alzheimer’s disease (AD) is characterized by progressive memory loss and impaired cognitive function
We have demonstrated that transgenic mice expressing familial AD (FAD)-linked presenilin 1 (PS1) variants in a ubiquitous manner exhibit impairments in EE-mediated proliferation and neuronal differentiation of Adult hippocampal neural stem cells (AHNSCs) [12], and that these AHNSC phenotypes are driven by non cell-autonomous mechanisms that require mutant PS1 expression in microglia [12] and excitatory neurons [13]
We report that the conditioned medium of microglia obtained from PS1 M146V KI mice impairs the proliferation of wild type adult hippocampal neural progenitor cell (AHNPC)
Summary
Alzheimer’s disease (AD) is characterized by progressive memory loss and impaired cognitive function. PS are the catalytic components of the γ-secretase complex and expression of PS1 variants leads to elevations in the ratio of Aβ42/Aβ40 peptides, leading to nucleation, oligomerization and neuropathogenicity of Aβ42 peptides [2] Notwithstanding this important aspect of pathogenesis mediated by FAD-linked PS1 variants, a number of studies have revealed that PS1 influences multiple signaling pathways and have more global effects on neuronal function and plasticity [3]. Adult hippocampal neural stem cells (AHNSCs), a self-renewing cell population in the subgranular layer (SGL) of the dentate gyrus (DG), functionally mature into neurons and integrate into the hippocampal circuitry [4] This process of adult neurogenesis has been implicated in hippocampal function, learning and memory, and adaptation to novel environments, stress response, depression, injury or disease [5,6,7]. We have demonstrated that transgenic mice expressing FAD-linked PS1 variants in a ubiquitous manner exhibit impairments in EE-mediated proliferation and neuronal differentiation of AHNSCs [12], and that these AHNSC phenotypes are driven by non cell-autonomous mechanisms that require mutant PS1 expression in microglia [12] and excitatory neurons [13]
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