DCP-LA, a New Strategy for Alzheimer's Disease Therapy

Abstract

Keywords DCP-LA PKCí µí¼€ Protein tyrosine phosphatase 1B Akt GSK-3í µí»½ Tau Alzheimer's disease ABSTRACT Alzheimer's disease (AD) is characterized by extensive deposition of amyloid í µí»½ (Aí µí»½) and formation of neurofibrillary tangles (NFTs) consisting of hyperphosphorylated Tau. So far, a variety of AD drugs targeting Aí µí»½ have been developed, but ended in failure. A recent focus on AD therapy, therefore, is development of Tau-targeted drugs. Aí µí»½ activates glycogen synthase kinase-3í µí»½ (GSK-3í µí»½), that plays a central role in Tau phosphorylation, responsible for NFT formation. The linoleic acid derivative DCP-LA has been developed as a promising drug for AD therapy. DCP-LA serves as a selective activator of PKCí µí¼€ and a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B). DCP-LA restrains Tau phosphorylation efficiently due to PKCí µí¼€-mediated direct inactivation of GSK-3í µí»½, to PKCí µí¼€/Akt-mediated inactivation of GSK-3í µí»½, and to receptor tyrosine kinase/insulin receptor substrate 1/phosphoinositide 3-kinase/3-phosphoinositide-dependent protein kinase 1/Akt-mediated inactivation of GSK-3í µí»½ in association with PTP1B inhibition. Moreover, DCP-LA ameliorates spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. Consequently, combination of PKCí µí¼€ activation and PTP1B inhibition must be an innovative strategy for AD therapy.