Metalloenzyme-like activity of Alzheimer's disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2).
ABSTRACT Beta-amyloid (Abeta) 1-42, implicated in the pathogenesis of Alzheimer's disease, forms an oligomeric complex that binds copper at a CuZn superoxide dismutase-like binding site. Abeta.Cu complexes generate neurotoxic H(2)O(2) from O(2) through Cu(2+) reduction, but the reaction mechanism has been unclear. We now report that Abeta1-42, when binding up to 2 eq of Cu(2+), generates the H(2)O(2) catalytically by recruiting biological reducing agents as substrates under conditions where the Cu(2+) or reducing agents will not form H(2)O(2) themselves. Cholesterol is an important substrate for this activity, as are vitamin C, L-DOPA, and dopamine (V(max) for dopamine = 34.5 nm/min, K(m) = 8.9 microm). The activity was inhibited by anti-Abeta antibodies, Cu(2+) chelators, and Zn(2+). Toxicity of Abeta in neuronal culture was consistent with catalytic H(2)O(2) production. Abeta was not toxic in cell cultures in the absence of Cu(2+), and dopamine (5 microm) markedly exaggerated the neurotoxicity of 200 nm Abeta1-42.Cu. Therefore, microregional catalytic H(2)O(2) production, combined with the exhaustion of reducing agents, may mediate the neurotoxicity of Abeta in Alzheimer's disease, and inhibitors of this novel activity may be of therapeutic value.
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ABSTRACT: Alzheimer's disease (AD) is a progressive and neurodegenerative disorder that induces dementia in older people. It was first reported in 1907 by Alois Alzheimer, who characterized the disease as causing memory loss and cognitive impairment. Pathologic characteristics of AD are β-amyloid plaques, neurofibrillary tangles and neurodegeneration. Current therapies only target the relief of symptoms using various drugs, and do not cure the disease. Recently, stem cell therapy has been shown to be a potential approach to various diseases, including neurodegenerative disorders, and in this review, we focus on stem cell therapies for AD.International Journal of Molecular Sciences 10/2014; 15(10):19226-19238. · 2.34 Impact Factor
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ABSTRACT: Aggregated β-amyloid peptides play key roles in the development of Alzheimer's disease, and recent evidence suggests that microbial particles, among others, can facilitate their polymerization. Bacterial enzymes, however, have been proved to be beneficial in degrading pathological fibrillar structures in clinical settings, such as strepto-kinases in resolving blood-clots. The purpose of this study was to investigate the ability of bacterial substances to effectively hydrolyze β-amyloid peptides. Degrading products of several proteinases from Bacillus pumilus were evaluated using MALDI-TOF mass-spectrometry, and their toxicity was assessed in vitro using cell-culture assays and morphological studies. These enzymes have proved to be non-toxic and were demonstrated to cleave through the functional domains of β-amyloid peptide. By yielding inactive fragments, proteinases of Bacillus pumilus may be used as candidate anti-amyloid agents.Brain Research Bulletin 09/2014; · 2.97 Impact Factor