Taurine in drinking water recovers learning and memory in the adult APP/PS1 mouse model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a lethal progressive neurological disorder affecting the memory. Recently, US Food and Drug Administration mitigated the standard for drug approval, allowing symptomatic drugs that only improve cognitive deficits to be allowed to accelerate on to clinical trials. Our study focuses on taurine, an endogenous amino acid found in high concentrations in humans. It has demonstrated neuroprotective properties against many forms of dementia. In this study, we assessed cognitively enhancing property of taurine in transgenic mouse model of AD. We orally administered taurine via drinking water to adult APP/PS1 transgenic mouse model for 6 weeks. Taurine treatment rescued cognitive deficits in APP/PS1 mice up to the age-matching wild-type mice in Y-maze and passive avoidance tests without modifying the behaviours of cognitively normal mice. In the cortex of APP/PS1 mice, taurine slightly decreased insoluble fraction of Aβ. While the exact mechanism of taurine in AD has not yet been ascertained, our results suggest that taurine can aid cognitive impairment and may inhibit Aβ-related damages.

Figure 1. Structures of taurine and homotaurine.

Figure 2. Improvement in spatial and hippocampal learning behaviours in taurine-treated transgenic mice.

7-month old wild-type (Wt) and age-matched APP/PS1 transgenic (Tg) male mice were orally administered water or taurine (1,000 mg/kg/day) for 6 weeks (n = 8–10 per group). After 6 weeks, behavioural tests were administered to the 8.5-month old mice. (A) Y-maze. Average alternation (%) of each group of mice was calculated. (B) Passive avoidance. Average latency time in seconds for each group of mice was measured. One-way ANOVA followed by Bonferroni's post-hoc comparisons tests were performed in all statistical analyses (*P < 0.05, **P < 0.01, ***P < 0.001, n.s.: no significance).

Figure 3. Aβ burden tests in the hippocampi and whole brains in mice.

7-month old wild-type (Wt) or age-matched APP/PS1 transgenic (Tg) male mice were orally administrated water or taurine (1,000 mg/kg/day) for 6 weeks (n = 8–10 per group). (A) ThS-stained Aβ burden in whole brains (scale bar, 1 mm) and hippocampal regions (scale bar, 200 μm) of each group. (B) normalized (%) number, area or average size of Aβ burden to 8.5-month old mice level in whole brains. The mouse brain schematic diagram was adapted from the Mouse Brain Atlas (green box: regions of brain images). One-way ANOVA followed by Bonferroni's post-hoc comparisons tests were performed in all statistical analyses (*P < 0.05, **P < 0.01, ***P < 0.001, n.s.: no significance).

Figure 4. Biochemical analyses of GFAP and Aβ in the hippocampi and the cortices.

7-month old wild-type (Wt) and age-matched APP/PS1 transgenic (Tg) male mice were orally administered water or taurine (1,000 mg/kg/day) for 6 weeks (n = 8–10 per group). Immunohistochemical analyses of (A) hippocampal regions and (B) cortical regions of 8.5-month old mice were perfused and sectioned. Aβs in the brain sections were stained by 6E10 antibody and ThS. Aβ plaques with ThS staining (1st row): blue, All Aβs including APP (2nd row): green, GFAP was stained by anti-GFAP (3^rd row): red, DAPI: blue (a location indicator). The bottom rows show merged images with DAPI staining. Scale bars, 50 or 200 μm, respectively. The mouse brain schematic diagram was adapted from the Mouse Brain Atlas (green box: regions of brain images). (C) Quantifications of Aβ in brain lysates or (D) CSF Aβ analyses by sandwich-ELISA. Aβ-soluble (Sol.) fraction (sucrose-tris lysis buffer) and Aβ-insoluble (Insol.) fraction (guanidine-HCl lysis buffer) of brain lysates were analyzed. β-actin is a loading control. (E) Western blot analyses of brain lysates obtained from hippocampal and cortical regions. One-way ANOVA followed by Bonferroni's post-hoc comparisons tests were performed in all statistical analyses (*P < 0.05, **P < 0.01, ***P < 0.001, n.s.: no significance).