Amyloid-beta impairs development of neuronal progenitor cells by oxidative mechanisms.
Neuronal progenitor cells (NPCs) are being considered for treatment of neurodegenerative diseases associated with beta-amyloidosis: Alzheimer's disease (AD) and Down syndrome (DS). However, the neurotoxic properties of amyloid-beta peptide (Abeta) may impair survival and differentiation of transplanted NPCs. Hence, we studied the influence of Abeta on development of human NPCs--proliferation, migration, formation of colonies of neurons, formation processes--in culture. Pre-fibrillized human Abeta1-40 blocked development of neuronal colonies. NPC development was impaired in the presence of soluble Abeta1-40 (1.75-7 microM), and NPC differentiation into large and small neurons was altered, as demonstrated by morphometry. Antioxidant vitamin E partially abolished these effects, but not the reduced formation of neuronal processes. NPCs cultured with 7 microM Abeta1-40 accumulated Abeta monomers and oligomers and contained higher levels of protein carbonyls and lipid peroxidation products HNE and MDA. We suggest that Abeta1-40 impairs development of NPCs by oxidative damage. Hence, a prerequisite of successful neuroreplacement therapy using NPCs in AD and DS/AD may be removal of amyloid-beta and antioxidative treatment.
Mazur-Kolecka
B
B
Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA. BMKO_JFRA@msn.com
Golabek
A
A
Nowicki
K
K
Flory
M
M
Frackowiak
J
J
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000975:Antioxidants / Q000008:administration & dosage; D015153:Blotting, Western / Q000379:methods; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005333:Fetus; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D015227:Lipid Peroxidation / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D014810:Vitamin E / Q000008:administration & dosage
D016229:Amyloid beta-Peptides; D000975:Antioxidants; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D014810:Vitamin E; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine