The various aggregation states of β-amyloid 1–42 mediate different effects on oxidative stress, neurodegeneration, and BACE-1 expression

The amyloid cascade hypothesis suggests that the insoluble and fibrillar form of β-amyloid (Aβ) may play a primary pathogenic role in Alzheimer disease at the molecular level. However, neither the rate of dementia nor the extent of neuronal change seems to correlate with the levels of amyloidotic plaques (i.e., aggregated/fibrillar Aβ). Recent evidence suggests, however, that neurotoxicity may be exerted also by rather small soluble aggregates of Aβ, including oligomers. To characterize the mechanisms underlying toxicity mediated by the various aggregation states of Aβ peptides is then a major goal of research. In this work we investigated the effects of fibrillar, prefibrillar, and oligomeric Aβ1–42 on the induction of oxidative stress, cell death, and BACE-1 expression in NT2 neuronal cells. We found that prefibrillar and oligomeric Aβ1–42 resulted in a more dramatic increase in the oxidative stress markers 4-hydroxynonenal and hydrogen peroxide compared to fibrillar Aβ1–42. Moreover, increased oxidative stress levels also resulted in a more rapid and significant induction of both apoptotic and necrotic neuronal cell death. Accordingly, fibrillar Aβ1–42, but not the soluble nonfibrillar forms, was the only condition able to up-regulate BACE-1 expression and activity.