Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation.
In addition to its well-established role in gamma-secretase cleavage, presenilin (PS) also plays a role in regulating the stability of cytosolic beta-catenin, a protein involved in Wnt signaling. Several familial Alzheimer's disease-associated PS1 mutations have been shown to increase the stability of the signaling pool of beta-catenin, correlating with enhanced cell proliferation. Accordingly, we hypothesized that in the setting of PS1 mutations, abnormal activation of Wnt/beta-catenin signaling leads to increased cell division. We tested this hypothesis by examining whether there is evidence of increased neurogenesis in the hippocampus of adult transgenic mice that overexpress the PS1 A246E mutation. In PS1/PS2-deficient fibroblasts, expression of PS1 A246E Familial AD mutation failed to restore the rapid turnover of beta-catenin compared with wild-type PS1. We then examined whether the same mutation enhanced neurogenesis in vivo in adult hippocampus of PS1-deficient mice when restored by wild-type human PS1 (PS1(-/-)WT) or A246E PS1 mutation (PS1(-/-)AE). The PS1 A246E mutation stimulated the proliferation of progenitor cells in the dentate gyrus of adult mice, as assessed by 5-bromo-2-deoxyuridine incorporation, but did not influence their survival or differentiation. These observations suggest that the PS1 A246E mutation influences cell growth putatively via abnormal beta-catenin signaling in vivo.
Department of Neurosciences, University of California-San Diego, School of Medicine, La Jolla, California 92093-0691, USA.
Nathalie L
NL
Chevallier
Salvador
S
Soriano
David E
DE
Kang
Eliezer
E
Masliah
Gloria
G
Hu
Edward H
EH
Koo
D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D053764:Presenilin-1; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D015534:Trans-Activators; D051176:beta Catenin