期刊
NEURON
卷 59, 期 4, 页码 568-580出版社
CELL PRESS
DOI: 10.1016/j.neuron.2008.07.033
关键词
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资金
- National Institute of Health [AG021494, AG027854]
- Edward H. Levi Fund
- Alzheimer's Association New Investigator Research
- Cure Alzheimer's Fund
- Brain Research Foundation
- Chicago Institute of Neurosurgery and Neuroresearch Foundation
- Adler Foundation
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.
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