Identification of Inhibitors Effective at Preventing Aggregation of the Amyloid-β Protein Involved in Alzheimer's Disease

Alzheimer's disease (AD) is a progressive degenerative disorder that is characterized by loss of memory, confusion, and cognitive disabilities. One hallmark of AD is extracellular plaques in the brain. These plaques are composed primarily of amyloid-β (Aβ) protein, which aggregates from the harmless Aβ monomer. Once it has aggregated into amyloid fibrils, Aβ gains toxicity and can affect the surrounding neuronal cells. The objective of the research is to identify inhibitors which prevent the monomer from undergoing aggregation and assess their effectiveness.

Aggregation of SEC-purified Aβ monomer was induced by agitation and typically showed a lag phase, followed by quick growth, then ending with a stationary phase. Aggregation assays were performed in the absence and presence of inhibitors to assess the ability of inhibitors to prolong the lag phase. Inhibitors were screened at a concentration five-fold in excess of Aβ monomer, then effective inhibitors were examined at lower concentrations, including equimolar with the monomer, to identify the most effective inhibitors.

Nine cyclic inhibitors were tested. Two inhibitors considerably increased the lag time to aggregate formation. One exhibited diminishing effectiveness as the concentration approached equimolar with monomer. Another compound retained its effectiveness at equimolar concentrations, but lost activity at substoichiometric concentrations.