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Factor V activator from Daboia russelli russelli venom destabilizes ?-amyloid aggregate, the hallmark of Alzheimer disease.

ABSTRACT: Formation of plaque by fibrils of ?-amyloid (A?) peptide in the brain is the characteristic feature of Alzheimer disease (AD). Inhibition of the process of aggregate formation from A?-monomer and destabilization of the aggregate could be useful for prevention and propagation of the disease respectively. Russell's viper venom (RVV) contains protein(s) that destabilize A? aggregates as revealed from the thioflavin T assay. The active component was identified as factor V activator (RVV-V). Among the possible mechanisms of destabilization, RVV-V-mediated proteolysis was ruled out from mass spectrometric data and the thioflavin T assay. The alternate hypothesis that small peptides derived from RVV-V destabilize the aggregate is better supported by experimental results. Six small peptides were synthesized using RVV-V as the template, and three unrelated peptides were synthesized to serve as controls. Destabilization of A? aggregate by these peptides was studied using spectrofluorometric assays, atomic force microscopy, transmission electron microscopy, and confocal microscopy. Among the peptides, CTNIF and the mixture of the six peptides were most potent in converting the aggregates to the monomeric state and thus, preventing cytotoxicity in SH-SY5Y human neuroblastoma cells. The control peptides failed to show similar effects. Moreover, some of these peptides are stable in blood for 24 h. Therefore, these venom-derived peptides offer an encouraging opportunity to prevent amyloidosis and may provide information to combat AD.

SUBMITTER: Bhattacharjee P

PROVIDER: S-EPMC3798527 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Factor V activator from Daboia russelli russelli venom destabilizes β-amyloid aggregate, the hallmark of Alzheimer disease.

Bhattacharjee Payel P Bhattacharyya Debasish D

The Journal of biological chemistry 20130828 42

Formation of plaque by fibrils of β-amyloid (Aβ) peptide in the brain is the characteristic feature of Alzheimer disease (AD). Inhibition of the process of aggregate formation from Aβ-monomer and destabilization of the aggregate could be useful for prevention and propagation of the disease respectively. Russell's viper venom (RVV) contains protein(s) that destabilize Aβ aggregates as revealed from the thioflavin T assay. The active component was identified as factor V activator (RVV-V). Among th ...[more]

PMID: 23986449

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Project description:Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) involve the abnormal accumulation in the brain of filaments composed of both three-repeat (3R) and four-repeat (4R) (3R/4R) tau isoforms. To probe the molecular basis for AD's tau filament propagation and to improve detection of tau aggregates as potential biomarkers, we have exploited the seeded polymerization growth mechanism of tau filaments to develop a highly selective and ultrasensitive cell-free tau seed amplification assay optimized for AD (AD real-time quaking-induced conversion or AD RT-QuIC). The reaction is based on the ability of AD tau aggregates to seed the formation of amyloid fibrils made of certain recombinant tau fragments. AD RT-QuIC detected seeding activity in AD (n = 16) brains at dilutions as extreme as 107-1010-fold, but was 102-106-fold less responsive when seeded with brain from most cases of other types of tauopathy with comparable loads of predominant 3R or 4R tau aggregates. For example, AD brains had average seeding activities that were orders of magnitude higher than Pick disease brains with predominant 3R tau deposits, but the opposite was true using our previously described Pick-optimized tau RT-QuIC assay. CTE brains (n = 2) had seed concentrations comparable to the weakest of the AD specimens, and higher than 3 of 4 specimens with 3R/4R primary age-related tauopathy. AD seeds shared properties with the tau filaments found in AD brains, as AD seeds were sarkosyl-insoluble, protease resistant, and reactive with tau antibodies. Moreover, AD RT-QuIC detected as little as 16 fg of pure synthetic tau fibrils. The distinctive seeding activity exhibited by AD and CTE tau filaments compared to other types of tauopathies in these seeded polymerization reactions provides a mechanistic basis for their consistent propagation as specific conformers in patients with 3R/4R tau diseases. Importantly, AD RT-QuIC also provides rapid ultrasensitive quantitation of 3R/4R tau-seeding activity as a biomarker.

Dataset Information

Factor V activator from Daboia russelli russelli venom destabilizes ?-amyloid aggregate, the hallmark of Alzheimer disease.

Publications

Factor V activator from Daboia russelli russelli venom destabilizes β-amyloid aggregate, the hallmark of Alzheimer disease.

Similar Datasets

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