Preprint Review Version 1 This version is not peer-reviewed

Linoleic Acid Derivative DCP-LA Prevents Tau Phosphorylation by Targeting GSK-3β

Version 1 : Received: 17 January 2018 / Approved: 17 January 2018 / Online: 17 January 2018 (05:26:21 CET)

How to cite: Nishizaki, T. Linoleic Acid Derivative DCP-LA Prevents Tau Phosphorylation by Targeting GSK-3β. Preprints 2018, 2018010148 (doi: 10.20944/preprints201801.0148.v1). Nishizaki, T. Linoleic Acid Derivative DCP-LA Prevents Tau Phosphorylation by Targeting GSK-3β. Preprints 2018, 2018010148 (doi: 10.20944/preprints201801.0148.v1).

Abstract

Abnormal Tau phosphorylation and aggregation into neuronal paired helical filaments and neurofibrillary tangles cause tauopathies, a class of neurodegenerative diseases, that include Alzheimer’s disease, frontotemporal dementia and parkinsonism linked to chromosome 17, progressive supranuclear palsy, Pick's disease, and corticobasal degeneration. Glycogen synthase kinase-3β (GSK-3β) is the most critical kinase to phosphorylate Tau. We have developed the linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), with cyclopropane rings instead of cis-double bonds, as an anti-dementia drug. DCP-LA serves as a selective activator of PKCε and a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B). DCP-LA prevents Tau phosphorylation due to PKCε-mediated direct inactivation of GSK-3β, to PKCε/Akt-mediated inactivation of GSK-3β, and to receptor tyrosine kinase-mediated inactivation of GSK-3β in association with PTP1B inhibition. DCP-LA targeting GSK-3β, thus, could become a valid drug for treatment of tauopathies.

Subject Areas

DCP-LA; PKCε; protein tyrosine phosphatase 1B; Akt; GSK-3β; tauopathy

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