Expression of familial Alzheimer's disease-linked human presenilin 1 variants impair enrichment-induced adult hippocampal neurogenesis.
Presenilin 1 (PS1) plays a critical role in neurogenesis both during development and in the adult. We recently reported that ubiquitous expression of familial, early-onset Alzheimer's disease-linked PS1 mutants impairs enrichment-induced proliferation and neurogenesis of hippocampal neural progenitor cells (NPCs) in a non-cell autonomous manner. The impairments in proliferation and neurogenesis are, at least in part, due to alterations in the levels of specific chemokines and growth factors secreted from microglia expressing familial Alzheimer's disease-linked PS1 variants. To test our hypothesis that the fate of hippocampal NPCs in PS1 mutant mice is largely determined by cellular factors produced within the niche itself, we are examining the fate of NPCs from hippocampi of wild-type human PS1 or PS1 mutant mice that are marked with green fluorescent protein and BrdU following transplantation into heterologous hosts. In parallel, we have generated transgenic mice that harbor a transgene encoding the PS1DeltaE9 variant flanked with loxP sites that can be conditionally deleted in a temporal and/or spatial manner using specific cre driver lines. These studies will allow us to assess the contributions of varying cell types within the hippocampal stem cell niche that express mutant PS1 to NPC proliferation and differentiation.
Veeraraghavalu
Karthikeyan
K
Department of Neurobiology, University of Chicago, 947 E. 58th Street, AB 308, Chicago, IL 60637, USA.
Choi
Se Hoon
SH
Sisodia
Sangram S
SS
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D005786:Gene Expression Regulation / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics*; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D051381:Rats
C508853:PSEN1 protein, human; D053764:Presenilin-1; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine