Dataset Information

Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation.

ABSTRACT: Presenilin 1 (PS1) regulates environmental enrichment (EE)-mediated neural progenitor cell (NPC) proliferation and neurogenesis in the adult hippocampus. We now report that transgenic mice that ubiquitously express human PS1 variants linked to early-onset familial Alzheimer's disease (FAD) neither exhibit EE-induced proliferation, nor neuronal lineage commitment of NPCs. Remarkably, the proliferation and differentiation of cultured NPCs from standard-housed mice expressing wild-type PS1 or PS1 variants are indistinguishable. On the other hand, wild-type NPCs cocultured with primary microglia from mice expressing PS1 variants exhibit impaired proliferation and neuronal lineage commitment, phenotypes that are recapitulated with mutant microglia conditioned media in which we detect altered levels of selected soluble signaling factors. These findings lead us to conclude that factors secreted from microglia play a central role in modulating hippocampal neurogenesis, and argue for non-cell-autonomous mechanisms that govern FAD-linked PS1-mediated impairments in adult hippocampal neurogenesis.

SUBMITTER: Choi SH

PROVIDER: S-EPMC3489017 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation.

Choi Se Hoon SH Veeraraghavalu Karthikeyan K Lazarov Orly O Marler Seoan S Ransohoff Richard M RM Ramirez Jan Marino JM Sisodia Sangram S SS

Neuron 20080801 4

Presenilin 1 (PS1) regulates environmental enrichment (EE)-mediated neural progenitor cell (NPC) proliferation and neurogenesis in the adult hippocampus. We now report that transgenic mice that ubiquitously express human PS1 variants linked to early-onset familial Alzheimer's disease (FAD) neither exhibit EE-induced proliferation, nor neuronal lineage commitment of NPCs. Remarkably, the proliferation and differentiation of cultured NPCs from standard-housed mice expressing wild-type PS1 or PS1 v ...[more]

PMID: 18760694

Similar Datasets

Project description:BackgroundMutations in the PSEN1 and PSEN2 genes are the major cause of familial Alzheimer's disease. Previous studies demonstrated that Presenilin (PS), the catalytic subunit of γ-secretase, is required for survival of excitatory neurons in the cerebral cortex during aging. However, the role of PS in inhibitory interneurons had not been explored.MethodsTo determine PS function in GABAergic neurons, we generated inhibitory neuron-specific PS conditional double knockout (IN-PS cDKO) mice, in which PS is selectively inactivated by Cre recombinase expressed under the control of the endogenous GAD2 promoter. We then performed behavioral, biochemical, and histological analyses to evaluate the consequences of selective PS inactivation in inhibitory neurons.ResultsIN-PS cDKO mice exhibit earlier mortality and lower body weight despite normal food intake and basal activity. Western analysis of protein lysates from various brain sub-regions of IN-PS cDKO mice showed significant reduction of PS1 levels and dramatic accumulation of γ-secretase substrates. Interestingly, IN-PS cDKO mice develop age-dependent loss of GABAergic neurons, as shown by normal number of GAD67-immunoreactive interneurons in the cerebral cortex at 2-3 months of age but reduced number of cortical interneurons at 9 months. Moreover, age-dependent reduction of Parvalbumin- and Somatostatin-immunoreactive interneurons is more pronounced in the neocortex and hippocampus of IN-PS cDKO mice. Consistent with these findings, the number of apoptotic cells is elevated in the cerebral cortex of IN-PS cDKO mice, and the enhanced apoptosis is due to dramatic increases of apoptotic interneurons, whereas the number of apoptotic excitatory neurons is unaffected. Furthermore, progressive loss of interneurons in the cerebral cortex of IN-PS cDKO mice is accompanied with astrogliosis and microgliosis.ConclusionOur results together support a cell-autonomous role of PS in the survival of cortical interneurons during aging. Together with earlier studies, these findings demonstrate a universal, essential requirement of PS in the survival of both excitatory and inhibitory neurons during aging.

Dataset Information

Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation.

Publications

Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets