Study of the structural and physical properties of small molecule and nanoparticle inhibitors of amyloid-beta protein fibril formation in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia in the elderly. The instances of AD are rapidly increasing and there is no cure currently available for this devastating disease. Current therapies for the disease allow AD patients to delay or mitigate the symptoms in order to improve their quality of life; however, these therapies do not halt disease progression.;The primary component of the amyloid plaques characteristic of AD brain is the fibrillar form of the amyloid-beta protein (Abeta). The 'amyloid cascade hypothesis' links aggregation of this protein to the pathogenesis of AD. Monomeric forms of Abeta aggregate to form fibrils that are deposited in AD brain and consequently cause neuronal cell death. Thus, inhibition of Abeta aggregation has become a prime therapeutic strategy for this currently unpreventable disease.;In the current study, we have identified novel inhibitors of Abeta self-assembly including a julolidine derivative, coumarin analogs, and surface modified gold nanoparticles. To gain insight into the mechanistic action of these inhibitors, the inhibition of fibril formation from monomeric protein is compared to the inhibition of the two distinct mechanisms of growth for soluble Abeta aggregation intermediates: elongation and association. Results with the julolidine derivative suggest that this compound binds the lateral surface of on-pathway intermediates to prevent their association with other aggregates, which is required for further assembly into mature fibrils. Functionalization of the coumarin base structure altered inhibitory capabilities of the coumarin analogs and influenced the point at which an inhibitor can intervene within the nucleation dependent Abeta aggregation pathway. Gold nanoparticles, which are non-toxic, were identified as novel inhibitors of Abeta aggregation and results demonstrated that their surface charge had a significant effect upon the manner in which nanoparticles influence the aggregation process. Together, these results will facilitate the design of potential inhibitors of Abeta fibril formation that may lead to advances in the creation of therapeutic agents against AD.