Oxidative stress increases levels of endogenous amyloid‐β peptides secreted from primary chick brain neurons

Abstract

SummaryOxidative damage is associated with Alzheimer's disease and mild cognitive impairment, but its relationship to the development of neuropathological lesions involving accumulation of amyloid-β β β β (Aβ β β β ) peptides and hyperphosphorylated tau protein remains poorly understood. We show that inducing oxidative stress in primary chick brain neurons by exposure to sublethal doses of H 2 O 2 increases levels of total secreted endogenous Aβ β β β by 2.4-fold after 20 h. This occurs in the absence of changes to intracellular amyloid precursor protein or tau protein levels, while heatshock protein 90 is elevated 2.5-fold. These results are consistent with the hypothesis that aging-associated oxidative stress contributes to increasing Aβ β β β generation and upregulation of molecular chaperones in Alzheimer's disease. Key words: Alzheimer's disease; amyloid-β β β β peptide; oxidative stress.Extracellular plaques containing aggregated amyloid-β (A β ) peptides and intracellular neurofibrillary tangles of hyperphosphorylated tau protein are the two salient pathological hallmarks of the Alzheimer's disease (AD) brain. A β is generated by consecutive cleavages of amyloid precursor protein (APP) by β -secretase ( β -site APP cleaving enzyme 1, BACE 1) and the γ -secretase protein complex of which presenilin is the catalytic subunit (Hardy, 2006). Familial mutations in APP or presenilin lead to increased generation and/or aggregation of A β peptides and cause early-onset AD (Hardy, 2006). Aggregated A β interferes with synaptic plasticity and causes neuronal cell death (Lambert et al ., 1998;Townsend et al. , 2006;Kayed et al ., 2004;Wogulis et al ., 2005). This and other evidence supports the amyloid hypothesis which postulates that toxicity exerted by aggregated A β initiates AD, with synaptic dysfunction, neurofibrillary pathology and oxidative injury constituting downstream events (Hardy, 2006). A number of studies, however, suggest that oxidative damage occurs in mild cognitive impairment (MCI) and early stages of sporadic AD, before widespread plaque and tangle development (Sayre et al ., 1997;Butterfield et al ., 2006;Nunomura et al ., 2006;Williams et al ., 2006;Lovell & Markesbery, 2008). Stress-activated BACE 1 and γ -secretase have been proposed to contribute to the deposition of A β peptides in sporadic AD (Tamagno et al ., 2008). Supporting this idea, expression and activity of BACE 1 is elevated in the brains of sporadic AD patients (Fukumoto et al ., 2002;Holsinger et al ., 2002 (Wen et al ., 2004;Tesco et al ., 2007), all of which are events associated with increased sporadic AD risk. These findings suggest that oxidative stress is upstream of A β in AD and that A β might be generated as a compensatory response in neurons attempting to attenuate oxidative stress (Smith et al ., 2002;Lee et al ., 2006). In addition, neurofibrillary degeneration may exacerbate the oxidative damage and elevation of A β (Yan et al ., 1995). In this context, mutations in APP that cause familial AD or in tau that cause fro...

The Role of 6-Gingerol on Inhibiting Amyloid β Protein-Induced Apoptosis in PC12 Cells

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Oxidative stress up‐regulates presenilin 1 in lipid rafts in neuronal cells

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Alzheimer's disease: Effects of β-amyloid on mitochondria

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