One-compound-multi-targets at amyloid β cascade offered by Bis(7)-Cognitin, a novel anti-Alzheimer's dimer

Abstract

Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. The neuropathological hallmarks of AD are senile plaques, which are extracellular deposits predominantly composed of fibrillar amyloid β peptide (Aβ), and intracellular neurofibrillary tangles composed of filamentous aggregates called paired helical filaments of hyperphosphorylated tau protein. Aβ is proposed to play a key role in the pathogenesis of AD. Therefore, treatments targeting the biosynthesis, oligomerization/aggregation, and toxicity of Aβ are likely to be the promising disease-modifying therapeutics. Bis(7)-Cognitin, one of our promising anti-Alzheimer's dimers, has previously been shown to possess potent acetylcholinesterase (AChE) inhibition, memory-enhancement, and neuroprotection against several stimuli that go beyond the inhibition of AChE. Our recent studies have further demonstrated that bis(7)-Cognitin exerts profound neuroprotective effects by targeting the multiple stages of the Aβ pathological cascade of AD, i.e. the biosynthesis, oligomerization/aggregation and toxicity of Aβ. These findings may offer not only a new and clinically significant modality as to how the agent exerts neuroprotective effects, but also a novel direction to rationally develop one-compound-multi-targets drugs for the prevention and treatment of AD, even of other neurodegenerative diseases.