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Mutant presenilin 1 expression in excitatory neurons impairs enrichment-mediated phenotypes of adult hippocampal progenitor cells.

ABSTRACT: Inheritance of mutant presenilin 1 genes (PSEN1) encoding presenilin 1 (PS1)variants causes autosomal dominant forms of familial Alzheimer's disease (FAD). We previously reported that ubiquitous expression of FAD-linked PS1 variants in mice impairs environmental enrichment (EE)-induced proliferation and neuronal commitment of adult hippocampal neural progenitor cells (AHNPCs). Notably, the self-renewal and differentiation properties of cultured AHNPCs expressing either human PS1 wild-type or PS1 variants were identical, suggesting that accessory cells within the hippocampal niche expressing PS1 variants may modulate AHNPC phenotypes in vivo. We now report that nontransgenic mouse AHNPCs transduced with retroviruses harboring cDNAs that encode either human PS1 wild-type or FAD-linked PS1 variants show no differences in EE-mediated proliferation and neuronal differentiation. Moreover, conditional inactivation of a mutant PS1 transgene in type-1 primary progenitor cells failed to rescue impairments of EE-induced proliferation, survival, or neurogenesis. In contrast, conditional inactivation of the mutant PS1 transgene in excitatory neurons of the mouse forebrain largely rescued the deficits in EE-induced proliferation and survival of AHNPCs, but not their differentiation into mature neuronal phenotypes. These results persuasively argue for a noncell autonomous effect of FAD-linked PS1 mutants on EE-mediated adult hippocampal neurogenesis.

SUBMITTER: Veeraraghavalu K

PROVIDER: S-EPMC3670351 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Mutant presenilin 1 expression in excitatory neurons impairs enrichment-mediated phenotypes of adult hippocampal progenitor cells.

Veeraraghavalu Karthikeyan K Sisodia Sangram S SS

Proceedings of the National Academy of Sciences of the United States of America 20130514 22

Inheritance of mutant presenilin 1 genes (PSEN1) encoding presenilin 1 (PS1)variants causes autosomal dominant forms of familial Alzheimer's disease (FAD). We previously reported that ubiquitous expression of FAD-linked PS1 variants in mice impairs environmental enrichment (EE)-induced proliferation and neuronal commitment of adult hippocampal neural progenitor cells (AHNPCs). Notably, the self-renewal and differentiation properties of cultured AHNPCs expressing either human PS1 wild-type or PS1 ...[more]

PMID: 23674689

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Project description:Presenilin 1 (PS1) and Presenilin 2 (PS2) are predominantly known as the catalytic subunits of the γ-secretase complex that generates the amyloid-β (Aβ) peptide, the major constituent of the senile plaques found in the brain of Alzheimer's disease (AD) patients. Apart from their role in γ-secretase activity, a growing number of cellular functions have been recently attributed to PSs. Notably, PSs were found to be enriched in mitochondria-associated membranes (MAMs) where mitochondria and endoplasmic reticulum (ER) interact. PS2 was more specifically reported to regulate calcium shuttling between these two organelles by controlling the formation of functional MAMs. We have previously demonstrated in mouse embryonic fibroblasts (MEF) an altered mitochondrial morphology along with reduced mitochondrial respiration and increased glycolysis in PS2-deficient cells (PS2KO). This phenotype was restored by the stable re-expression of human PS2. Still, all these results were obtained in immortalized cells, and one bottom-line question is to know whether these observations hold true in central nervous system (CNS) cells. To that end, we carried out primary cultures of PS1 knockdown (KD), PS2KO, and PS1KD/PS2KO (PSdKO) neurons and astrocytes. They were obtained from the same litter by crossing PS2 heterozygous; PS1 floxed (PS2+/-; PS1flox/flox) animals. Genetic downregulation of PS1 was achieved by lentiviral expression of the Cre recombinase in primary cultures. Strikingly, we did not observe any mitochondrial phenotype in PS1KD, PS2KO, or PSdKO primary cultures in basal conditions. Mitochondrial respiration and membrane potential were similar in all models, as were the glycolytic flux and NAD+/NADH ratio. Likewise, mitochondrial morphology and content was unaltered by PS expression. We further investigated the differences between results we obtained here in primary nerve cells and those previously reported in MEF cell lines by analyzing PS2KO primary fibroblasts. We found no mitochondrial dysfunction in this model, in line with observations in PS2KO primary neurons and astrocytes. Together, our results indicate that the mitochondrial phenotype observed in immortalized PS2-deficient cell lines cannot be extrapolated to primary neurons, astrocytes, and even to primary fibroblasts. The PS-dependent mitochondrial phenotype reported so far might therefore be the consequence of a cell immortalization process and should be critically reconsidered regarding its relevance to AD.

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Mutant presenilin 1 expression in excitatory neurons impairs enrichment-mediated phenotypes of adult hippocampal progenitor cells.

Publications

Mutant presenilin 1 expression in excitatory neurons impairs enrichment-mediated phenotypes of adult hippocampal progenitor cells.

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