Anti-apoptotic proteins are oxidized by Aβ25–35 in Alzheimer's fibroblasts

Abstract

We have examined the effects of the beta-amyloid peptide (Abeta(25-35)) on fibroblasts derived from subjects with Alzheimer's disease (AD) and from age-matched controls. The peptide was significantly more cytotoxic to the AD-derived fibroblasts. The level of protein oxidation was also greater in the cells from AD subjects. Two-dimensional electrophoresis (2-DE) coupled with immunostaining for protein carbonylation revealed specific oxidation-sensitive proteins (OSPs) in both the control and AD-derived cells. Two specific OSPs were identified by mass spectrometry as heat shock protein 60 (HSP 60) and vimentin. Exposure of the cells to Abeta(25-35) resulted in a twofold increase in the level of oxidation of these two OSPs in the cells derived from controls, but a ninefold increase in their level of oxidation in the fibroblasts from AD subjects. These observations are of particular interest because of the proposed anti-apoptotic roles of both HSP 60 and vimentin and our recent observation that these same two proteins are particularly susceptible to oxidation in neuronally derived cells.

Redox Proteomics: A New Approach to Investigate Oxidative Stress in Alzheimer's Disease

“…The expression of HSP60 is significantly decreased in AD (Yoo et al, 2001). Also Aβ(25-35) induces oxidation of HSP60 in fibroblasts derived from AD patients (Choi et al, 2003). Taken together, oxidation of HSP60 is likely caused by the abnormal accumulation of Aβ.…”

Cell Stress Induced by the Parkinsonian Mimetic, 6-Hydroxydopamine, is Concurrent with Oxidation of the Chaperone, ERp57, and Aggresome Formation

“…In general, however, only subsets of proteins have been shown to be carbonylated, such as chaperones, cytoskeletal proteins, protein disulfide isomerases (PDIs), and various metabolic enzymes (1,5,7,34). Oxidation of these proteins, many of which are cell protective, may trigger downstream events such as UPR and apoptosis.…”

Alzheimer's Disease and Molecular Chaperones: Current Knowledge and the Future of Chaperonotherapy

“…In support of the neuroprotective effects of Hsp60, it has been demonstrated that in a human neuroblastoma cell line, induced expression of the chaperonin prevented intracellular -amyloid-induced inhibition of complex IV and consequently reduced apoptosis [84]. A 25-35 induced oxidation of Hsp60 in fibroblasts derived from AD patients [85] and, also, Hsp60 was oxidized by A 1-42 leading to a loss of function of the chaperonin, which caused an increase in protein misfolding and aggregation [86]. Again, this would be a chaperonopathy by defect.…”