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

Abstract

The 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.