Elevation of phospholipase C-beta 1 expression by amyloid-beta facilitates calcium overload in neuronal cells

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Amyloid-beta (A beta) has long been considered a key cause of neurodegeneration in the AD brain. Although the mechanisms underlying A beta-induced neurodegeneration are not fully understood, a number of recent studies have suggested that intracellular calcium overload mediates this process. In this study, we focused on the cellular function of phospholipase C-beta 1 (PLCB1), which regulates calcium signaling by mediating hydrolysis of phosphatidylinositol 4,5-bisphosphate through G-protein coupled receptor pathways. First, we confirmed that acetylcholine-induced calcium release from intracellular stores of SH-SY5Y cells was significantly increased with A beta 42 oligomer treatment. We further found that PLCB1 expression was upregulated in A beta 42-treated cells, and PLCB1 overexpression in SH-SY5Y cells elicited the calcium overload observed in A beta-treated cells. In addition, A beta 42 oligomer-induced calcium overload in SH-SY5Y cells was alleviated by knockdown of PLCB1, indicating that PLCB1 plays an essential role in the neurotoxic process initiated by A beta. The elevation of PLCB1 expression was confirmed in the brain tissues from the 5x familial AD (5xFAD) model mice. These findings suggest that PLCB1 may represent a potential therapeutic target for protecting neuronal cells against excitotoxicity in AD progression.