A defining feature of Alzheimer’s Disease (AD) is the presence of large deposits of amyloid-beta peptide (AB) in the brain. This accumulation of AB is widely regarded as one of the most prominent pathogenic mechanisms of AD. The amyloid cascade hypothesis describes the self-assembly of AB into a large range of species with differing sizes, conformations, and toxicities. In the past decade, extensive studies have implicated soluble intermediates of the AB cascade called oligomers as the primary causative agent behind the disorder. These small oligomers, rather than large, insoluble amyloid fibrils, cause the neuronal cell death and loss of function characteristic of the AD brain. Here, a unique approach to AD treatment is presented where pharmacological modulation of the AB equilibrium promotes AB fibrillogenesis to reduce the concentration of neurotoxic AB oligomers. Detailed biochemical studies revealed that [ald]SS31, an aladan analog of the blood-brain barrier permeable, mitoprotective drug Bendavia (SS31), is able to alter the AB equilibrium to favor the assembly of nontoxic amyloid fibrils. By accelerating fibril formation, [ald]SS31 decreases the prevalence of harmful amyloid intermediates and protects N2A cells from the inherent reactivity and neurotoxicity of AB oligomers, demonstrating potential as an AD therapeutic and supporting the oligomer toxicity hypothesis.
Third Award of $1,000