FAD-linked human Presenilin 1 variants impair environmental enrichment-induced hippocampal neural progenitor cell proliferation and differentiation in a non-cell-autonomous manner

By Se Hoon Choi, Karthikeyan Veeraraghavalu, Orly Lazarov, S. Marler, R. Ransohoff, J. Ramirez, Sangram S. Sisodia. 2008

170 citations recorded by the source corpus.

SUMMARY 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 co-cultured 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.

Subfields: Cellular and Molecular Neuroscience, Developmental Neuroscience, Neurology

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Citations in the corpus

Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions (2011, background): “…of human presenillin (PS) variants linked to early-onset familial Alzheimer's disease in microglia impairs proliferation and neuronal fate commitment (Choi et al., 2008), whereas deletion of PS1 in forebrain excitatory neurons affects enrichment-induced hippocampal neurogenesis (Feng et al., 2001).”
Neurodegenerative disease and adult neurogenesis (2011, background): “It is also important to note that, under certain circumstances, an enriched environment in APP and PSEN1 transgenic mice not only improves memory function but also reduces Ab deposition in the central nervous system (Lazarov et al., 2005).”
Induced Adult Neurogenesis plus BDNF Mimicks the Effects of Exercise on Cognition in an Alzheimer’s Mouse Model (2018, methodology): “Immunohistochemistry and immunofluorescent labeling were performed as described previously (54).”
Microglial physiology: unique stimuli, specialized responses. (2009, background): “The data supported an important role for microglia in regulating NSPCs during physiology and pathology (94, 95).”
Microglia: biology and pathology (2009, background): “microglia expressing FAD-linked PS1 variants impair proliferation of neural progenitor cells [32].”
Amyloid-β Peptide Protects Against Microbial Infection In Mouse and Worm Models of Alzheimer’s Disease (2016, methodology): “Immuno- and Thioflavin S–costained mouse sections Immunofluorescence labeling was performed as described previously (71).”
Heterogeneity of CNS myeloid cells and their roles in neurodegeneration (2011, background): “One study of mice expressing a mutant form of PS-1 uncovered a pathogenic pathway by which microglia were stimulated by the presence of the transgene product to produce secreted factors that inhibited neurogenesis in the hippocampal dentate gyru”
Presenilin 1 mutants impair the self-renewal and differentiation of adult murine SVZ-neuronal progenitors via cell autonomous mechanisms involving Notch signaling (2010, methodology): “In contrast to standard housing conditions, we reported that expression of FAD-linked PS1 impairs the proliferation and differentiation of adult hippocampal NPCs following environmental enrichment and factors secreted by microglial cells are at least, in part, responsible for these phenotypes, thus ”
Exercise and the brain: something to chew on (2009, background): “Transgenic mice that express human presenilin-1 variants linked to early-onset familial AD [55] and a mouse model for Huntington's disease [56] do not show exercise induced neurogenesis.”
Adult hippocampal neurogenesis and its role in Alzheimer's disease (2011, background): “Enriched environment (EE)-induced proliferation and neuronal differentiation of hippocampal progenitor cells in mice harboring transgenes encoding the FADlinked human PS1 variant PS1ΔE9 or PS1M146L were significantly impaired, although the impairment was at least in part mediated by soluble factors ”