Inositol 1,4,5-trisphosphate Receptor Modulators Protect Neurons Against Beta-amyloid Peptides (25-35 and 1-42)-induced Toxicity

Abstract

Beta-amyloid (Aβ) peptides have been proposed to play important roles in the pathogenesis of Alzheimer’s disease. It is well known that Aβ peptides are toxic to neurons in vivo and in vitro. Recent studies have proposed that neuronal cell death induced by Aβ peptides could be due to its action on disrupting intracellular calcium homeostasis. In the present study, we aim to study the roles of IP3R in Aβ peptides neurotoxicity by using three IP3R modulators, FK506, 2-aminoethoxydiphenyl borate and Xestospongin C. Release of lactate dehydrogenase, visualization of apoptotic nuclei stained with 4',6'-diamidino-2-phenylindole (DAPI), PARP cleavage, and caspase-2 and caspase-3 activities were used to evaluated the toxic effects of Aβ peptides on primary cortical neurons. We found that all three IP3R modulators significantly attenuated Aβ peptides neurotoxicity, associated with the decrease of caspase-2 and caspase-3 activities. Taken together, these results reveal that IP3R plays important roles in Aβ peptides toxicity and could be an important pharmacological target in future therapeutic approaches. Supported by Hong Kong Research Grant Council (HKU 7305/00M) and The Molecular Institute of Technology for drug synthesis and discovery (AOE)