Involvement of α7 nAChR Signaling Cascade in Epigallocatechin Gallate Suppression of β-Amyloid-Induced Apoptotic Cortical Neuronal Insults

Excessive generation and accumulation of the beta-amyloid (A beta) peptide in selectively vulnerable brain regions is a key pathogenic event in the Alzheimer's disease (AD), while epigallocatechin gallate (EGCG) is a very promising chemical to suppress a variety of A beta-induced neurodegenerative disorders. However, the precise molecular mechanism of EGCG responsible for protection against neurotoxicity still remains elusive. To validate and further investigate the possible mechanism involved, we explored whether EGCG neuroprotection against neurotoxicity of A beta is mediated through the alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) signaling cascade. It was shown in rat primary cortical neurons that short-term treatment with EGCG significantly attenuated the neurotoxicity of A beta(1-42), as demonstrated by increased cell viability, reduced number of apoptotic cells, decreased reactive oxygen species (ROS) generation, and downregulated caspase-3 levels after treatment with 25-mu M A beta(1-42). In addition, EGCG markedly strengthened activation of alpha 7nAChR as well as its downstream pathway signaling molecules phosphatidylinositol 3-kinase (PI3K) and Akt, subsequently leading to suppression of Bcl-2 downregulation in A beta-treated neurons. Conversely, administration of alpha 7nAChR antagonist methyllycaconitine (MLA; 20 mu M) to neuronal cultures significantly attenuated the neuroprotection of EGCG against A beta-induced neurototoxicity, thus presenting new evidence that the alpha 7nAChR activity together with PI3K/Akt transduction signaling may contribute to the molecular mechanism underlying the neuroprotective effects of EGCG against A beta-induced cell death.