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.
Highlights
The microtubule-associated protein tau plays a role in stabilizing microtubules and promoting their self-assembly from tubulin subunits [1, 2]
Tau is normally a highly soluble protein and mainly found in axons in adult neurons, intracellular inclusions of abnormally modified aggregated tau appear in neurons and glial cells in a range of neurodegenerative diseases collectively known as tauopathies, which include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration, Pick’s disease
To obtain rTg4510 mice for this study, tetO-MAPT P301L mice carrying a responder transgene consisting of a tetracycline-operon–responsive element placed upstream of a cDNA encoding human fourrepeat tau with the P301L mutation were crossed with mice from the CaMKII-tTA mouse line carrying an activator transgene that consisted of the tet-off open reading frame placed downstream of Ca2+-calmodulin kinase II promoter elements
Summary
The microtubule-associated protein tau plays a role in stabilizing microtubules and promoting their self-assembly from tubulin subunits [1, 2]. The intracellular inclusions contain abnormally hyperphosphorylated tau self-assembled in a β-sheet conformation [1,2,3]. Tau pathology in rTg4510 mice fed with Shiga-Y5. The introduction of the C57BL/6 strain into the rTg4510 mouse background has been reported to minimally alter the presentation of tau pathology of the original phenotype, without losing fidelity of the original phenotype [15]. Two to four mice were housed per standard laboratory cage on wood shavings. They were fed a standard chow diet and maintained at 23 ̊C under a 12-h light/dark cycle (lights on for the hours 08:00–20:00) with free access to water and food in a specific pathogen free animal facility
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