Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors

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.

TREM2 variants and risk of Alzheimer’s disease: a meta-analysis

“…Genetic studies have identified a number of genetic risk factors for AD, including amyloid precursor protein (APP), presenilin 1 (PSEN1), apolipoprotein E (APOE), ATPbinding cassette, subfamily A, member 7 (ABCA7), phosphatidylinositol-binding clathrin assembly protein (PICALM), complement receptor 1 (CR1), clusterin gene (CLU), and bridging integrator 1 (BIN1) [3][4][5][6][7][8][9][10]. Recently, many groups reported the association between rare genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) and the risk for sporadic AD [11,12].…”

Complex regulation of γ-secretase: from obligatory to modulatory subunits

“…Other Aβ-based therapies, such as immunotherapy and autophagic restoration, are being explored for AD as well (Lemere, 2013 ; Li et al, 2013 ). In addition to mice (Eimer and Vassar, 2013 ; Veeraraghavalu et al, 2013 ), other models have been investigated for AD studies (Mccoll et al, 2012 ; Do Carmo and Cuello, 2013 ), which help to elucidate the role of γ-secretase in pathogenesis. Recently, it has been suggested that a set of γ-secretase product peptides in the cerebrospinal fluid may serve as biomarkers for AD (Hata et al, 2012 ; Rosén et al, 2013 ).…”

γ‐Secretase in microglia – implications for neurodegeneration and neuroinflammation

“…In a co‐culture model with neuronal progenitor cells, primary microglia from FAD PS1 mutant mice showed lower stimulation of (wild‐type) neuronal progenitor cells proliferation as compared to microglia from PS1 wild‐type cells, and this effect was associated with altered secretion of soluble factors by PS1 mutant microglia (Veeraraghavalu et al . ). Together, these studies indicate complex roles of γ‐secretase in the regulation of intracellular signal transduction pathways and functions of microglia (Fig.…”