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

The origin of many neurodegenerative disorderslike Alzheimer’s Disease (AD) lies in protein processing failures,which leads to protein aggregation and accumulation as amyloidfibrils. Abnormal accumulation and aggregation of beta amyloidpeptide (Aβ) eventually lead to the formation and cerebraldeposition of amyloid plaques, the major pathological hallmarkin AD. Aβ1-40 and Aβ1-42 are the predominant components ofsenile plaques formed in AD brain. The aggregation of Aβ isassociated with neurodegeneration, loss of cognitive ability, andpremature death. Understanding the aggregation mechanism andhow to inhibit aggregate formation is therefore crucial. In light ofthe proposed link between oxidative stress, unregulated immuneresponse and neurodegeneration, it is suggested that use ofantioxidants may be beneficial for inhibiting Aβ fibrillogenesis.Therefore, endogenous and dietary antioxidants may offer aprotective or even therapeutic alternative against amyloidosis. Inthis study, several compounds isolated from natural products arescreened for the in vitro antiamyloidogenic activity. Novelelectrospray ionization (ESI) mass spectrometry (MS)-basedmethodologies are employed to assess the noncovalentinteractions between the Aβ and isolated components fromnatural products. The specificity and the stability of thesenoncovalent complexes were examined under differentexperimental conditions, whereas their relative binding strengthwas assessed. In addition, MS proteolytic mapping was employedto provide information on the noncovalent binding site of thebioactive molecule on the Aβ residues. This may shed some lightinto the mechanisms of AD pathology and provide insights intonovel agents that can be employed towards prevention or eventreatment of AD