Regucalcin confers resistance to amyloid‐β toxicity in neuronally differentiated PC12 cells

• Published in: FEBS open bio 2018-03, Vol.8 (3), p.349-360
• Main Authors: Murata, Tomiyasu, Yamaguchi, Masayoshi, Kohno, Susumu, Takahashi, Chiaki, Kakimoto, Mitsumi, Sugimura, Yukiko, Kamihara, Mako, Hikita, Kiyomi, Kaneda, Norio
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; amyloid‐β; Apoptosis; Breast cancer; Calcium (intracellular); Calcium homeostasis; Calcium signalling; Calcium-binding protein; Caspase; Cell activation; Cell differentiation; CRISPR; Cytotoxicity; Endoplasmic reticulum; Gene expression; Growth factors; Homeostasis; Intracellular signalling; Kinases; Lipid peroxidation; mitochondrial dysfunction; Neurodegeneration; Neurodegenerative diseases; Neurotoxicity; Nitric oxide; Nitric-oxide synthase; Oxidative stress; Pancreatic cancer; Pathogenesis; Penicillin; Pheochromocytoma cells; Phosphatase; Proteins; reactive nitrogen species; Reactive oxygen species; Reagents; regucalcin; Senile plaques; β-Amyloid
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12374

Amyloid‐β (Aβ), a primary component of amyloid plaques, has been widely associated with the pathogenesis of Alzheimer's disease. The Ca2+‐binding protein regucalcin (RGN) plays multiple roles in maintaining cell functions by regulating intracellular calcium homeostasis, various signaling pathways, and gene expression systems. Here, we investigated the functional role of RGN against Aβ‐induced cytotoxicity in neuronally differentiated PC12 cells. Overexpression of RGN reduced Aβ‐induced apoptosis by reducing mitochondrial dysfunction and caspase activation. It also attenuated Aβ‐induced reactive oxygen species production and oxidative damage and decreased Aβ‐induced nitric oxide (NO) overproduction, upregulation of inducible NO synthase by nuclear factor‐κB, and nitrosative damage. Interestingly, the genetic disruption of RGN increased the susceptibility of neuronally differentiated PC12 cells to Aβ toxicity. Thus, RGN possesses antioxidant activity against Aβ‐induced oxidative and nitrosative stress and may play protective roles against Aβ‐induced neurotoxicity in Alzheimer's disease. Upon treatment with amyloid‐β (Aβ), the Ca2+‐binding protein regucalcin (RGN) inhibits overproduction of mitochondrial reactive oxygen species and the subsequent oxidative damage, restores mitochondrial function, and blocks apoptosis in neuronally differentiated PC12 cells. RGN also inhibits Aβ‐induced nuclear factor‐κB activation and attenuates nitric oxide (NO)‐induced nitrosative damage from inducible NO synthase. Thus, RGN exerts protective effect against Aβ toxicity.