Increased GABBR2 Expression on Cell Membranes Causes Increased Ca2 + Inward Flow, Associated with Cognitive Impairment in Early Alzheimer's Disease.

Alzheimer's disease (AD) and mild cognitive impairment (MCI) are a serious global public health problem. The aim of this study was to analyze the key molecular pathological mechanisms that occur in early AD progression as well as MCI. Expression profiling data from brain homogenates of 8 normal volunteers, and 6 patients with prodromal AD who had developed MCI were analyzed, and the data were obtained from GSE12685. Further, overexpression of GABBR2 was achieved in human neuroblastoma cell lines SH-SY5Y and BE(2)-M17 using expression plasmid transfection. GABBR2 was significantly overexpressed in brain tissues of patients with prodromal AD who had developed MCI, as compared to normal brains. Moreover, GABBR2 overexpressing cells showed a significant increase in intracellular Ca²⁺ concentration, a large amount of reactive oxygen species production, a large opening of the mitochondrial permeability transition pore and a significant increase in apoptosis compared with control cells. GABBR2 overexpression was significantly involved in early AD progression and MCI by causing cellular events such as intracellular Ca²⁺ imbalance, oxidative stress, and mitochondrial dysfunction.