272022 Dihydropyridines Inhibit Amyloid-β Aggregation and Alter the Morphology of Amyloid-β Fibrils Associated with Alzheimer's Disease
Alzheimer’s disease (AD), one of the most widespread neurodegenerative diseases, is characterized by the accumulation of intracellular neurofibrillary tangles and extracellular amyloid plaques. Symptoms include confusion, language skill breakdown, long-term memory loss and other cognitive impairments. Unfortunately, current therapies cannot halt or slow AD pathogenesis. It has been proposed that amyloid plaque formation initiates pathological events that culminate in neuronal loss. These amyloid plaques are composed primarily of fibrillar amyloid-β protein (Aβ), formed as a result of the aggregation of Aβ monomer. Thus, understanding of the process of Aβ aggregation as well as the structures of Aβ fibrils formed is necessary to comprehend AD pathology and provide a rational design of compounds to prevent formation of pathogenic Aβ species.
Dihydropyridines (DHPs) are a group of small molecules containing at least one pyridine ring and one phenyl ring. These compounds, which can act as calcium channel blockers, are FDA approved for treatment of hypertension. DHPs are promising drugs for AD as a result of their aromatic nature. Numerous in vitro studies have reported that small molecules containing aromatic centers are potential candidates to alter Aβ fibril formation. In this research, four DHPs, as well as their metabolic products, are investigated for their ability to alter different stages of Aβ aggregation.
The DHPs studied all showed some ability to inhibit aggregation of 20 µM Aβ monomer. For most compounds, this activity was observed at a compound concentration in excess of Aβ. However, nicardipine exhibited an IC50 value of 5.7 µM, demonstrating its strong inhibitory capability. The ability of DHPs to inhibit growth of pre-formed Aβ aggregates was also examined. Only three DHPs showed significant inhibition at later stages of Aβ aggregation. Results were confirmed by transmission electron microscopy (TEM), which demonstrates that the densities of fibrils correlate closely with monomer aggregation results. Furthermore, variations of fibril morphology were observed and could be correlated with the effect of DHPs in later stages of aggregation. Recent studies showed that by changing Aβ aggregation mechanisms, Aβ fibrils exhibit morphological differences, and these differences are predicted to alter their physiological activity. In summary, DHPs are promising compounds that reduce aggregate formation and alter fibril structures, thus potentially attenuating physiological activity and disease pathogenesis.
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