Amyloid-β impairs development of neuronal progenitor cells by oxidative mechanisms

Abstract

Neuronal progenitor cells (NPCs) are being considered for treatment of neurodegenerative diseases associated with β-amyloidosis: Alzheimer's disease (AD) and Down syndrome (DS). However, the neurotoxic properties of amyloid-β peptide (Aβ) may impair survival and differentiation of transplanted NPCs. Hence, we studied the influence of Aβ on development of human NPCs – proliferation, migration, formation of colonies of neurons, formation processes – in culture. Pre-fibrillized human Aβ1–40 blocked development of neuronal colonies. NPC development was impaired in the presence of soluble Aβ1–40 (1.75–7 μM), 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 μM Aβ1–40 accumulated Aβ monomers and oligomers and contained higher levels of protein carbonyls and lipid peroxidation products HNE and MDA. We suggest that Aβ1–40 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-β and antioxidative treatment.