Use of Mass Spectrometric Approaches to Tackle Challenges in Drug Discovery: The Beta-Amyloid Paradigm

Abstract

AbstractThe origin of many neurodegenerative disorders like Alzheimer’s Disease (AD) lies in protein processing failures, which leads to protein aggregation and accumulation as amyloid fibrils. Abnormal accumulation and aggregation of beta amyloid peptide (Aβ) eventually lead to the formation and cerebral deposition of amyloid plaques, the major pathological hallmark in AD. Aβ1-40 and Aβ1-42 are the predominant components of senile plaques formed in AD brain. The aggregation of Aβ is associated with neurodegeneration, loss of cognitive ability, and premature death. Understanding the aggregation mechanism and how to inhibit aggregate formation is therefore crucial. In light of the proposed link between oxidative stress, unregulated immune response and neurodegeneration, it is suggested that use of antioxidants may be beneficial for inhibiting Aβ fibrillogenesis. Therefore, endogenous and dietary antioxidants may offer a protective or even therapeutic alternative against amyloidosis. In this study, several compounds isolated from natural products are screened for the in vitro antiamyloidogenic activity. Novel electrospray ionization (ESI) mass spectrometry (MS)-based methodologies are employed to assess the noncovalent interactions between the Aβ and isolated components from natural products. The specificity and the stability of these noncovalent complexes were examined under different experimental conditions, whereas their relative binding strength was assessed. In addition, MS proteolytic mapping was employed to provide information on the noncovalent binding site of the bioactive molecule on the Aβ residues. This may shed some light into the mechanisms of AD pathology and provide insights into novel agents that can be employed towards prevention or even treatment of AD.