Molecular characterization of multi-targets by bis(7)-tacrine at amyloid beta cascade associated with Alzheimer's disease.

摘要

Amyloid beta protein (Abeta) is supposed to play a key role in the pathogenesis of Alzheimer's disease (AD). Therefore, treatments targeting at the biosynthesis, aggregation, and toxicity of Abeta are likely to be the promising disease-modifying therapeutics. Bis(7)-tacrine, a promising anti-Alzheimer's dimer, has been shown to possess superior AChE inhibition, memory-enhancement and neuroprotection against several stimuli. In my thesis research, it has been first found that bis(7)-tacrine, similar to protein kinase C (PKC) activator PMA, significantly reduces the generation of both secreted and intracellular Abeta in Neuro2a APPswe cells by affecting the processing of amyloid beta precursor protein (APP), which is evidenced by stimulating alpha-secretase and inhibiting beta-secretase (BACE-1), but not affecting the activity of gamma-secretase. Furthermore, it has been found that bis(7)-tacrine differentially modulating the phosphorylations of different isozymes of PKC and PKC inhibitor can significantly reverse the change of APP processing and the reduction of Abeta generation induced by bis(7)-tacrine.;Next, it has been found that bis(7)-tacrine, similar to nimodipine, a blocker of L-type voltage-dependent Ca2+ channels (VDCCs), elicits the marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis, which is independent of AChE inhibition and cholinergic transmission. Further, bis(7)-tacrine and nimodipine reverse Abeta-triggered intracellular Ca2+ increase. Concurrently, bis(7)-tacrine significantly reduces the augmentation of high voltage-activated inward calcium currents induced by Abeta. These results suggest that bis(7)-tacrine might attenuate Abeta-induced neuronal apoptosis by regulating L-type VDCCs.;In addition, bis(7)-tacrine attenuates the oligomerization of Abeta in vitro, which might also contributes to the neuroprotection of bis(7)-tacrine in protecting against Abeta-induced neurotoxicity.;In summary, bis(7)-tacrine exerts superior neuroprotective effects by targeting at the multiple-stages of the amyloid pathological cascade of AD, i.e. the biosynthesis, aggregation and toxicity of Abeta, which 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 multiple-targets drugs for the prevention and treatment of various neurodegenerative diseases.