Affiliation:
1. School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
Abstract
Calcium homeostasis plays a vital role in protecting against Alzheimer’s disease (AD). In this study, amyloid-β (Aβ)-induced C. elegans models of AD were used to elucidate the mechanisms underlying calcium homeostasis in AD. Calcium acetate increased the intracellular calcium content, exacerbated Aβ1–42 aggregation, which is closely associated with oxidative stress, aggravated neuronal degeneration and dysfunction, and shortened the lifespan of the C. elegans models. Ethylene glycol tetraacetic acid (EGTA) and nimodipine were used to decrease the intracellular calcium content. Both EGTA and nimodipine showed remarkable inhibitory effects on Aβ1–42 aggregations by increasing oxidative stress resistance. Moreover, both compounds significantly delayed the onset of Aβ-induced paralysis, rescued memory deficits, ameliorated behavioral dysfunction, decreased the vulnerability of two major (GABAergic and dopaminergic) neurons and synapses, and extended the lifespan of the C. elegans AD models. Furthermore, RNA sequencing of nimodipine-treated worms revealed numerous downstream differentially expressed genes related to calcium signaling. Nimodipine-induced inhibition of selective voltage-gated calcium channels was shown to activate other calcium channels of the plasma membrane (clhm-1) and endoplasmic reticulum (unc-68), in addition to sodium-calcium exchanger channels (ncx-1). These channels collaborated to activate downstream events to resist oxidative stress through glutathione S-transferase activity mediated by HPGD and skn-1, as verified by RNA interference. These results may be applied for the treatment of Alzheimer’s disease.
Funder
Natural Science Foundation of Jiangsu Province
Subject
Cell Biology,Aging,General Medicine,Biochemistry
Cited by
2 articles.
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