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Study of tau pathology in male rTg4510 mice fed with a curcumin derivative Shiga-Y5.

ABSTRACT: Intracellular inclusions of aggregated tau appear in neurons and glial cells in a range of neurodegenerative diseases known as tauopathies. Inhibition of pathological changes in tau is a therapeutic target for tauopathy. We recently synthesized a novel curcumin derivative, named Shiga-Y5, and showed that Shiga-Y5 inhibited cognitive impairment and amyloid deposition in a mouse model of Alzheimer's disease. Here we investigated whether Shiga-Y5 inhibited cognitive impairment and tau accumulation in a mouse model of tauopathy, rTg4510. The rTg4510 mouse is a bitransgenic mouse model that uses a system of responder and activator transgenes to express human four-repeat tau with the P301L mutation. This strain is obtained by crossing tetO-MAPT*P301L mouse line (on a FVB/NJ background) with CaMKII-tTA mouse line (on a C57BL/6J background). Male rTg4510 mice and wild-type mice were fed with a standard chow diet with or without Shiga-Y5 (500 ppm) for 4 months. Behavioral tests were conducted from 5.5 months of age, and the mice were sacrificed at 6 months of age. There were no significant changes in behavioral performance in rTg4510 mice fed with SY5-containing chow diet compared with rTg4510 mice fed with control chow diet. Histological and biochemical analyses also showed no significant alterations in tau accumulation by the treatment with SY5. One of noticeable finding in this study was that rTg4510 mice on a F1 female FVB/NJ x male C57BL/6J background showed more severe tau accumulation than rTg4510 mice on a F1 female C57BL/6J x male FVB/NJ background. Further studies to clarify the mechanisms underlying tau aggregation may help to develop therapeutic approaches aimed at preventing this pathological feature.

SUBMITTER: Yanagisawa D

PROVIDER: S-EPMC6283544 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Study of tau pathology in male rTg4510 mice fed with a curcumin derivative Shiga-Y5.

Yanagisawa Daijiro D Hamezah Hamizah Shahirah HS Durani Lina Wati LW Taguchi Hiroyasu H Tooyama Ikuo I

PloS one 20181206 12

Intracellular inclusions of aggregated tau appear in neurons and glial cells in a range of neurodegenerative diseases known as tauopathies. Inhibition of pathological changes in tau is a therapeutic target for tauopathy. We recently synthesized a novel curcumin derivative, named Shiga-Y5, and showed that Shiga-Y5 inhibited cognitive impairment and amyloid deposition in a mouse model of Alzheimer's disease. Here we investigated whether Shiga-Y5 inhibited cognitive impairment and tau accumulation ...[more]

PMID: 30521594

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Project description:Hyperphosphorylation of microtubule-associated protein tau is a distinct feature of neurofibrillary tangles (NFTs) that are the hallmark of neurodegenerative tauopathies. O-GlcNAcylation is a lesser known post-translational modification of tau that involves the addition of N-acetylglucosamine onto serine and threonine residues. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models. Clarifying the underlying mechanism by which OGA inhibition leads to the reduction of pathological tau and identifying translatable measures to guide human dosing and efficacy determination would significantly facilitate the clinical development of OGA inhibitors for the treatment of tauopathies.Genetic and pharmacological approaches are used to evaluate the pharmacodynamic response of OGA inhibition. A panel of quantitative biochemical assays is established to assess the effect of OGA inhibition on pathological tau reduction. A "click" chemistry labeling method is developed for the detection of O-GlcNAcylated tau.Substantial (>80%) OGA inhibition is required to observe a measurable increase in O-GlcNAcylated proteins in the brain. Sustained and substantial OGA inhibition via chronic treatment with Thiamet G leads to a significant reduction of aggregated tau and several phosphorylated tau species in the insoluble fraction of rTg4510 mouse brain and total tau in cerebrospinal fluid (CSF). O-GlcNAcylated tau is elevated by Thiamet G treatment and is found primarily in the soluble 55 kD tau species, but not in the insoluble 64 kD tau species thought as the pathological entity.The present study demonstrates that chronic inhibition of OGA reduces pathological tau in the brain and total tau in the CSF of rTg4510 mice, most likely by directly increasing O-GlcNAcylation of tau and thereby maintaining tau in the soluble, non-toxic form by reducing tau aggregation and the accompanying panoply of deleterious post-translational modifications. These results clarify some conflicting observations regarding the effects and mechanism of OGA inhibition on tau pathology, provide pharmacodynamic tools to guide human dosing and identify CSF total tau as a potential translational biomarker. Therefore, this study provides additional support to develop OGA inhibitors as a treatment for Alzheimer's disease and other neurodegenerative tauopathies.

Dataset Information

Study of tau pathology in male rTg4510 mice fed with a curcumin derivative Shiga-Y5.

Publications

Study of tau pathology in male rTg4510 mice fed with a curcumin derivative Shiga-Y5.

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