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

Tomoyuki Nishizaki

doi:10.29245/2572.942x/2017/9.1159

Abstract

Alzheimer’s disease (AD) is characterized by extensive deposition of amyloid β (Aβ) and formation of neurofibrillary tangles (NFTs) consisting of hyperphosphorylated Tau. So far, a variety of AD drugs targeting Aβ have been developed, but ended in failure. A recent focus on AD therapy, therefore, is development of Tau-targeted drugs. Aβ activates glycogen synthase kinase-3β (GSK-3β), 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 PKCe and a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B). DCP-LA restrains Tau phosphorylation efficiently due to PKCe-mediated direct inactivation of GSK-3β, to PKCe/Akt-mediated inactivation of GSK-3β, and to receptor tyrosine kinase/insulin receptor substrate 1/phosphoinositide 3-kinase/3-phosphoinositide-dependent protein kinase 1/Akt-mediated inactivation of GSK-3β 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 PKCβ activation and PTP1B inhibition must be an innovative strategy for AD therapy.

Highlights

Accumulating evidence has pointed to the role of amyloid β (Aβ), a main body of amyloid plaques, and Tau protein, a main body of neurofibrillary tangles (NFTs), in the pathogenesis of Alzheimer’s disease (AD)
Aβ1-42 activates glycogen synthase kinase-3β (GSK-3β) by reducing Ser[9] phosphorylation and increases Tau phosphorylation at Ser202/Thr[205] and Ser[396], and the effects of Aβ1-42 are clearly neutralized by DCP-LA32
DCP-LA ameliorates spatial learning and memory decline in 5xFAD mice, that occurs in parallel with GSK-β activation and an increase in Tau phosphorylation, but such effect is not obtained with galanthamine, that is clinically used for treatment of mild to moderate AD32

Summary

Introduction

Accumulating evidence has pointed to the role of amyloid β (Aβ), a main body of amyloid (senile) plaques, and Tau protein, a main body of neurofibrillary tangles (NFTs), in the pathogenesis of Alzheimer’s disease (AD). Activates GSK-3β by decreasing serine phosphorylation as a result of phosphoinositide 3-kinase (PI3K) inhibition/ inactivation[24]. Pyk[238], that binds to SH2 and SH3 domain-containing proteins like Src kinases, and Fyn[22] activate GSK-3β by phosphorylating at Tyr[216] directly (Figure 3). Tau-targeting drugs insulin or insulin-like growth-factor 1(IGF1) binds to and activates the RTK insulin receptor involving GSK-3β inactivation.

Results

Conclusion