THESIS
2007
xxi, 149 leaves : ill. (some col.) ; 30 cm
Abstract
Amyloid beta protein (Aβ) 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 Aβ 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 Aβ in Neuro2a APPswe cells by affecting the processing of amyloid β precursor protein (APP), which is evidenced by stimulating α-secretase and inhibiting β-secretase (BACE-1), but not af...[
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Amyloid beta protein (Aβ) 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 Aβ 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 Aβ in Neuro2a APPswe cells by affecting the processing of amyloid β precursor protein (APP), which is evidenced by stimulating α-secretase and inhibiting β-secretase (BACE-1), but not affecting the activity of γ-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 Aβ 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 Ca
2+ channels (VDCCs), elicits the marked reduction of both fibrillar and soluble oligomeric forms of Aβ-induced apoptosis, which is independent of AChE inhibition and cholinergic transmission. Further, bis(7)-tacrine and nimodipine reverse Aβ-triggered intracellular Ca
2+ increase. Concurrently, bis(7)-tacrine significantly reduces the augmentation of high voltage-activated inward calcium currents induced by Aβ. These results suggest that bis(7)-tacrine might attenuate Aβ-induced neuronal apoptosis by regulating L-type VDCCs.
In addition, bis(7)-tacrine attenuates the oligomerization of Aβ in vitro, which might also contributes to the neuroprotection of bis(7)-tacrine in protecting against Aβ-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 Aβ, 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.
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