The various aggregation states of beta-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 beta-amyloid (A beta) 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 A beta). Recent evidence suggests, however, that neurotoxicity may be exerted also by rather small soluble aggregates of A beta, including oligomers. To characterize the mechanisms underlying toxicity mediated by the various aggregation states of A beta peptides is then a major goal of research. In this work we investigated the effects of fibrillar, prefibrillar, and oligomeric A beta(1-42) on the induction of oxidative stress, cell death, and BACE-1 expression in NT2 neuronal cells. We found that prefibrillar and oligomeric A beta(1-42) resulted in a more dramatic increase in the oxidative stress markers 4-hydroxynonenal and hydrogen peroxide compared to fibrillar A beta(1-42). Moreover, increased oxidative stress levels also resulted in a more rapid and significant induction of both apoptotic and necrotic neuronal cell death. Accordingly, fibrillar A beta(1-42), but not the soluble nonfibrillar forms, was the only condition able to up-regulate BACE-1 expression and activity.
Tamagno
Elena
E
General Pathology Section, Department of Experimental Medicine and Oncology, University of Turin, Corso Raffaello 30, 10125 Turin, Italy. elena.tamagno@unito.it
Bardini
Paola
P
Guglielmotto
Michela
M
Danni
Oliviero
O
Tabaton
Massimo
M
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001483:Base Sequence; D016923:Cell Death; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016229:Amyloid beta-Peptides; D017931:DNA Primers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human