Linoleic Acid Derivative DCP-LA Sheds Light on Treatment of Alzheimer�s Disease

Special Article - Alzheimer’s Disease

Alzheimer’s Disease. Gerontol Geriatr Res. 2017; 3(2): 1032.

Linoleic Acid Derivative DCP-LA Sheds Light on Treatment of Alzheimer’s Disease

Nishizaki T*

Research Section, Innovative Bioinformation Research Organization, Japan

*Corresponding author: Tomoyuki Nishizaki, Research Section, Innovative Bioinformation Research Organization, 2-3-14 Katsuragi, Kita-ku, Kobe, Japan

Received: August 14, 2017; Accepted: September 06, 2017; Published: September 13, 2017

Abstract

Alzheimer’s Disease (AD) is a really tragic disease in which a human being loses human dignity. AD is characterized by extensive deposition of Amyloid β (Aβ) and formation of NFT. To date, none of Aβ-directed drugs for AD therapy have been successful and therefore, a current target for AD therapy focuses on Tau. Glycogen Syntheses Kinase-3β (GSK-3β) is a key protein kinase to phosphorylated Tau. The linoleic acid derivative 8-[2-(2-pentylcyclopropylmethyl)- cyclopropyl]-octanoic acid (DCP-LA) with the cyclopropane ring instead of the cis-double bond selectively activates PKCe, that directly inactivates GSK-3β, leading to suppression of Tau phosphorylation (pTau). DCP-LA-induced PKCe activation, alternatively, directly activates Akt, followed by inactivation of GSK3β, leading to suppression of pTau. DCP-LA also inhibits PTP1B, thereby relatively activating Receptor Tyrosine Kinase (RTK) and Insulin Receptor Substrate 1 (IRS-1), followed by the sequential activation of PhosphoInositide 3-Kinase (PI3K), Phosphoinositide-Dependent Kinase 1 (PDK1), and Akt. Then, activated Akt inactivates GSK-3b, leading to suppression of pTau. DCP-LA bearing synchronous PKCe activation and PTP1B inhibition, thus, could become a promising and novel drug for prevention and treatment of AD.

Keywords: DCP-LA; PKCe; PTP1B; GSK-3β; Alzheimer’s disease; Tau

Introduction

The number of Alzheimer’s Disease (AD) patients is considerably mounting in association with prolongation of life span and AD is currently a major burden on society. No beneficial anti-AD drug, however, has been provided as yet. The most urgent issue, therefore, is to develop drugs for AD.

We have found that cis-unsaturated free fatty acids such as arachidonic, linoleic and linolenic acid, persistently facilitates hippocampal synaptic transmission by targeting presynaptic nicotinic ACh receptor under the control of PKC. Cis-unsaturated free fatty acids, however, are promptly metabolized and decomposed before arriving in the brain, even though the fatty acids are orally or intravenously taken into the body. To resolve this problem, we have synthesized a variety of derivatives of cis-unsaturated free fatty acids, that exhibit stable bioactivities, and obtained the most effective compound 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]- octanoic acid (DCP-LA), a linoleic acid derivative with cyclopropane rings instead of cis-double bonds [1] (Figure 1).