title: Ganglioside-Dependent Neural Stem Cell Proliferation in Alzheimer's Disease Model Mice.
abstract: The aggregation and formation of amyloid plaques by amyloid β-peptides (Aβs) is believed to be one of the pathological hallmarks of Alzheimer's disease (AD). Intriguingly, Aβs have also been shown to possess proliferative effects on neural stem cells (NSCs). Many essential cellular processes in NSCs, such as fate determination and proliferation, are heavily influenced by cell surface glycoconjugates, including gangliosides. It has recently been shown that Aβ1-42 alters several key glycosyltransferases and glycosidases. To further define the effects of Aβs and to clarify the potential mechanisms of action of those peptides on NSCs, NSCs were cultured from embryonic brains of the double-transgenic mouse model of AD [B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J] coexpressing mutants of amyloid precursor protein (APPswe) and presenilin1 (PSEN1dE9). We found that Aβs not only promoted cell proliferation but also altered expression of several key glycogenes for glycoconjugate metabolism, such as sialyltransferases II and III (ST-II & -III) in AD NSCs. In addition, we found upregulation of epidermal growth factor receptor and Notch1 intracellular domain. Moreover, the increased expression of ST-II and -III coincided with the elevated levels of c-series gangliosides (A2B5+ antigens) in AD NSCs. Further, we revealed that epidermal growth factor signaling and gangliosides are necessary components on Aβ-stimulated NSC proliferation. Our present study has thus provided a novel mechanism for the upregulation of c-series ganglioside expression and increases in several NSC markers to account for the proliferative effect of Aβs on NSCs in AD mouse brain. These observations support the potential beneficial effects of Aβs and gangliosides in promoting neurogenesis in AD brain.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA Charlie Norwood VA Medical Center, Augusta, GA 30904, USA ryu@gru.edu.
authors.forename: Noah A
authors.initials: NA
authors.lastname: Koon
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Itokazu
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Yu
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism*; D016695:Glycosyltransferases / Q000378:metabolism; D006801:Humans; D008822:Mice, Transgenic; D009154:Mutation; D058953:Neural Stem Cells / Q000473:pathology / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005732:Gangliosides; C508853:PSEN1 protein, human; D053764:Presenilin-1; D004815:Epidermal Growth Factor; D016695:Glycosyltransferases
keywords: Alzheimer’s disease; amyloid β-peptide; cell proliferation; glycogene; glycosyltransferase; neural stem cell