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).

Figure 1: Chemical (A) and conformational structure (B) of DCP-LA.

    
    
    Figure 1:  Chemical (A) and conformational structure (B) of DCP-LA.

Beneficial anti-AD drugs require protection of neuronal apoptosis and facilitation of synaptic transmission relevant to cognitive functions. I show here that DCP-LA has the actions of both anti-apoptosis and cognitive enhancement.

Tau Phosphorylation is a Critical Factor for AD

Tau, which is abundantly expressed in neurons of the central nervous system, stabilizes microtubules by interacting with tubulin. When phosphorylated excessively, Tau becomes a trigger for tauopathies [2]. Tauopathies are a class of neurodegenerative diseases associated with aggregation of hyperphosphorylated Tau in an insoluble form in the brain, referred to as Neurofibrillary Tangles (NFT), which include AD, frontotemporal dementia and parkinsonism linked to chromosome 17, progressive supranuclear palsy, Pick’s disease, and corticobasal degeneration. AD is a really tragic disease in which a human being loses human dignity. AD is characterized by extensive deposition of amyloid β (A β) 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. Of protein kinases proposed glycogen synthese kinase-3β (GSK-3β) is a central executioner to induce Tau phosphorylation (pTau).

Emerging evidence has shown that Aβ serves as an initiator of AD and that Tau acts as an executioner of AD. Mild Cognitive Impairment (MCI) is a preliminary group of AD. Aging, inflammation, and stress activate GSK-3β, to phosphorylate Tau, causing MCI (Figure 2). Then, participation of Aβ further activates GSK-3β and accelerates pTau, leading to progression to AD from MCI (Figure 2). Accordingly, pTau is a key factor both for MCI and AD.

Figure 2: Pathogenesis of MCI and AD.

    
    
    Figure 2:  Pathogenesis of MCI and AD.

Interaction of DCP-LA with Protein Kinases and Protein Phosphatases

PKCe

PKC includes the conventional PKC isozymes a, βI, βII, and ?, the novel PKC isozymes d, €, ?, and ?, the atyoical PKC isozymes ?/λ and ?, and the PKC-like isozymes μ and ?. Of PKC isozymes DCP-LA selectively and directly activates PKCe in a Ca2+- and diacylglycerol-independent manner [3]. DCP-LA binds to PKCe at the Phosphatidylserine (PS) binding/associating sites Arg50 and Ile89 in the C2-like domain at the carboxyl-terminal end and the cyclopropane rings, respectively, which is distinct from the binding site (the C1 domain) of phorbol-12-myristate-13-acetate (PMA) [4] (Figure 3). Thus, the primary site of action of DCP-LA is PKCe.

Figure 3: A schematic diagram for DCP-LA-induced PKCe activation.

    
    
    Figure 3:  A schematic diagram for DCP-LA-induced PKCe activation.

Protein tyrosine phosphatase 1B (PTP1B) and protein phosphatase 1 (PP1)

DCP-LA inhibits PTP1B [5] and PP1 [6] through its direct interaction.

Akt

Akt1, which is preferentially expressed in neurons, is activated by being phosphorylated at Thr308 and Ser473. DCP-LA-induced PTP1B inhibition relatively activates Receptor Tyrosine Kinase (RTK) and Insulin Receptor Substrate 1 (IRS-1), followed by activation of Akt through a pathway along a RTK/IRS-1/phosphoinositide 3-kinase (PI3K)/phosphoinositide- dependent kinase 1 (PDK1)/Akt axis [7] (Figure 4). PKCe, activated by DCP-LA, directly activates Akt1 by phosphorylating at Ser473 [7] (Figure 4).

Figure 4: A schematic pathway underlying DCP-LA-induced Akt activation and GSK-3b inactivation.

    
    
    Figure 4:  A schematic pathway underlying DCP-LA-induced Akt activation
and GSK-3b inactivation.

GSK-3β

GSK-3β is activated and inactivated by being phosphorylated at Tyr216 and Ser9, respectively. Akt, that is activated by PKCe or through a RTK/IRS-1/PI3K/PDK1/Akt pathway in association with PTP1B inhibition under the influence of DCP-LA, inactivates GSK- 3β by phosphorylating at Ser9 [7] (Figure 4).

PKCe, activated by DCP-LA, inactivates GSK-3β by directly phosphorylating at Ser9 [7] (Figure 4).

DCP-LA Suppresses Tau Phosphorylation

Taken together, DCP-LA is capable of suppressing pTau by inactivating GSK-3β [7] (Figure 4). This indicates that DCP-LA has the potential to prevent and improve tauopathies including MCI and AD.

DCP-LA Protects Neuronal Cells from Apoptosis

Neuronal apoptosis in the neurodegenerative diseases such as AD and Parkinson’s disease is caused by Endoplasmic Reticulum (ER) stress or oxidative stress. DCP-LA inhibits Nitric Oxide (NO) stressinduced activation of caspase-3/-9 and apoptosis of neuronal cells [8]. This indicates that DCP-LA could prevent or delay progression of AD.

DCP-LA Facilitates Synaptic Transmission

Long-term Potentiation (LTP) is an established cellular model of learning and memory. DCP-LA activates presynaptic PKCe (Figure 5A-?), which promotes vesicular transport of a7 ACh receptor (a7R) towards the cell surface from the cytosol (Figure 5A-?), to increase a7R on the plasma membrane at the presynaptic terminals (Figure 5A-?). An increase in the number of a7R allows greater deal of Ca2+ influx (Figure 5A-?), which stimulates glutamate release from presynaptic terminals (Figure 5A-?), thereby facilitating synaptic transmission, leading to LTP [1,9-11].