(694g) Inhibition of Fibril Formation by the Amyloid-ß Protein Involved in Alzheimer's Disease

Authors: 
Soto-Ortega, D., University of South Carolina
Davis, T. J., University of South Carolina
Moss, M. A., University of South Carolina


Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia in the elderly, accounting for 70% of all diagnosed dementia cases. Current therapies for the disease allow AD patients to delay or mitigate the symptoms in order for them to have a better quality of life. However, these therapies do not stop the progression of the disease. Leading theories suggest that accumulation of amyloid plaques within the brain parenchyma is one of the first abnormalities in AD; thus, our study addresses inhibition of amyloid plaque formation.

The primary component of the amyloid plaques found in AD brain is the fibrillar form of the amyloid-ß protein (Aß). Aß is a short peptide proteolytic product of the transmembrane amyloid precursor protein (APP). The ?amyloid cascade hypothesis' states that self-assembly of monomeric Aß to form fibrils that are subsequently deposited in AD brain initiates a cascade of events involved in AD pathogenesis. Soluble aggregation intermediates, including oligomers and protofibrils, have been identified along the fibril formation pathway, and increasing evidence suggests that these soluble aggregates could be the primary cause of toxicity. Protofibrils can progress into fibrils via elongation by monomer deposition and lateral protofibril-protofibril association. Inhibition of Aß self-assembly at different points of the process has emerged as a therapeutic strategy for AD.

A number of small molecules have been identified as inhibitors of Aß self-assembly. However, little information about the relationship between the structures of potential inhibitors and their mechanism of inhibition has been reported. This study considers the hypothesis that small molecules containing aromatic structures will have different effects on specific mechanisms of Aß fibril formation as a result of differences in their interaction with Aß aggregates. A number of aromatic compounds have been evaluated for their ability to inhibit fibril formation from monomeric protein. The ability of these compounds to inhibit fibril formation from two distinct mechanisms of soluble aggregate growth was also assessed by identifying the compounds that exhibit effective inhibition in different mechanistic assays. We have identified key structural components that define effective inhibitors which may serve as active elements in future drug development.