(47c) Calcium Channel Blockers Can Attenuate Amyloid-Beta Self-Assembly: Potential as Dual-Action Drug for Alzheimer's Disease
Alzheimer's disease (AD) is one of the most widespread neurodegenerative diseases in the world. In the United States, there are 5.2 million people living with AD. As the disease advances, symptoms include confusion, language skill breakdown and long-term memory loss. Amyloid-beta (Aβ) is a small protein produced at low levels by normal brain metabolism. In AD, the amount of Aβ; becomes disorderly because of abnormal clearance or over production. Some researchers have proposed the amyloid cascade hypothesis to illustrate the pathogenesis of AD . In the hypothesis, aggregated forms of Aβ induce AD pathogenesis. As part of this cascade, Ca2+ channels near the neuronal synapses are disrupted and the destruction of calcium homeostasis leads to neurofibrillary tangle formation. These events will culminate cell in death.
Self-assembly of Aβ involves a multi-step pathway with several interconnected steps. From monomers, the protein presents a lag phase of nucleation, which is considered the rate limiting step, and then rapidly polymerizes to form small soluble aggregates, including oligomers and protofibrils. These intermediates grow by elongation via monomer addition and direct lateral association to form insoluble fibrils. Insoluble fibrils eventually deposit as plaques in the brains of AD patients.
It is known that Ca2+ overload can initiate the process of neuronal apoptosis. Furthermore, calcium entry along L-type Ca2+ channels leads to both calcium overload and mitochondrial disruption, which also activates apoptotic cell death . Therefore, drugs that block the entrance of Ca2+ through this type of Ca2+ channel are currently under investigation for AD therapy. If these drugs also stop Aβ aggregation, they would be dual-action drugs.
Dihydropyridines are verified L-type Ca2+ channel blockers commonly used in hypertension treatment. Moreover, nimodipine has the ability to prevent neurons from death induced by focal cerebral ischemia . Here, we introduce four dihydropyridine calcium channel blockers, amlodipine, felodipine, nicardipine, and nimodipine, to investigate the interaction between these compounds and different steps of Aβ self-assembly. In our experiments, we focus on four separate steps: monomer nucleation, oligomer formation, protofibril elongation, and protofibril association. These compounds all showed some abilities to regulate Aβ self-assembly, primarily at the stages of nucleation and oligomerization. These activities are observed at compound concentration in excess of Aβ. In summary, dihydropyridine derivatives are promising compounds that have the potential to interfere with two distinct pathogenesis mechanisms of AD.
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