title: Interruption of beta-catenin signaling reduces neurogenesis in Alzheimer's disease.
abstract: The neuronal loss associated with Alzheimer's disease (AD) affects areas of the brain that are vital to cognition. Although recent studies have shown that new neurons can be generated from progenitor cells in the neocortices of healthy adults, the neurogenic potential of the stem/progenitor cells of AD patients is not known. To answer this question, we compared the properties of glial progenitor cells (GPCs) from the cortices of healthy control (HC) and AD subjects. The GPCs from AD brain samples displayed reduced renewal capability and reduced neurogenesis compared with GPCs from HC brains. To investigate the mechanisms underlying this difference, we compared beta-catenin signaling proteins in GPCs from AD versus HC subjects and studied the effect of amyloid beta peptide (Abeta, a hallmark of AD pathology) on GPCs. Interestingly, GPCs from AD patients exhibited elevated levels of glycogen synthase kinase 3beta (GSK-3beta, an enzyme known to phosphorylate beta-catenin), accompanied by an increase in phosphorylated beta-catenin and a decrease in nonphosphorylated beta-catenin compared with HC counterparts. Furthermore. we found that Abeta treatment impaired the ability of GPCs from HC subjects to generate new neurons and caused changes in beta-catenin signaling proteins similar to those observed in GPCs from AD patients. Similar results were observed in GPCs isolated from AD transgenic mice. These results suggest that Abeta-induced interruption of beta-catenin signaling may contribute to the impairment of neurogenesis in AD progenitor cells.
authors.affiliation: Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, Arizona 85351, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: He
authors.forename: Yong
authors.initials: Y
authors.lastname: Shen
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D000367:Age Factors; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology*; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019081:O Antigens / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection / Q000379:methods; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011508:Chondroitin Sulfate Proteoglycans; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D039842:Neural Cell Adhesion Molecule L1; D019081:O Antigens; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D012794:Sialic Acids; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D051176:beta Catenin; C103469:polysialyl neural cell adhesion molecule; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3