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. 2018 Apr 24;8(1):6431.
doi: 10.1038/s41598-018-24741-0.

Reversal of memory and neuropsychiatric symptoms and reduced tau pathology by selenium in 3xTg-AD mice

Ann Van der Jeugd  1 , Arnaldo Parra-Damas  2 , Raquel Baeta-Corral  3 , Carlos M Soto-Faguás  2 , Tariq Ahmed  1   4 , Frank M LaFerla  5 , Lydia Giménez-Llort  3 , Rudi D'Hooge  1 , Carlos A Saura  6
Affiliations

Reversal of memory and neuropsychiatric symptoms and reduced tau pathology by selenium in 3xTg-AD mice

Ann Van der Jeugd et al. Sci Rep. .

Abstract

Accumulation of amyloid-β plaques and tau contribute to the pathogenesis of Alzheimer's disease (AD), but it is unclear whether targeting tau pathology by antioxidants independently of amyloid-β causes beneficial effects on memory and neuropsychiatric symptoms. Selenium, an essential antioxidant element reduced in the aging brain, prevents development of neuropathology in AD transgenic mice at early disease stages. The therapeutic potential of selenium for ameliorating or reversing neuropsychiatric and cognitive behavioral symptoms at late AD stages is largely unknown. Here, we evaluated the effects of chronic dietary sodium selenate supplementation for 4 months in female 3xTg-AD mice at 12-14 months of age. Chronic sodium selenate treatment efficiently reversed hippocampal-dependent learning and memory impairments, and behavior- and neuropsychiatric-like symptoms in old female 3xTg-AD mice. Selenium significantly decreased the number of aggregated tau-positive neurons and astrogliosis, without globally affecting amyloid plaques, in the hippocampus of 3xTg-AD mice. These results indicate that selenium treatment reverses AD-like memory and neuropsychiatric symptoms by a mechanism involving reduction of aggregated tau and/or reactive astrocytes but not amyloid pathology. These results suggest that sodium selenate could be part of a combined therapeutic approach for the treatment of memory and neuropsychiatric symptoms in advanced AD stages.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Sodium selenate ameliorates idiopathic and anxiety behaviors in 3xTg-AD mice. (A) Ethological assessment of WT and 3xTg-AD mice after chronic vehicle (Veh) or sodium selenate (Se) treatment. Loco: locomotion; seat: rearing seated; wall: rearing against the wall; free: rearing free; sift: sifting; groom: grooming; chew: chewing; still: stillness. (B) Evaluation of mice in the corner index task. Counts: number of visited corners or rearings. (C,D) Assessment of neophobia/anxiety in the dark-light test. 3xTg-AD mice show significantly increased latencies (C) and reduced transitions (D) towards the light compartment, a behavior reversed by Se treatment. (E) Evaluation of fear associative memory in the passive avoidance test. The reduced latencies to enter to the dark compartment were reversed in 3xTg-AD mice after Se treatment. (F,G) Assessment of well-being and social collaboration in the nest building test. 3xTg-AD mice showed a significant less nest-building ability than WT groups, while Se treatment increases nesting activity in 3xTg-AD mice (F) as observed in representative pictures of nests (G). Data represent mean ± s.e.m. Number of mice: WT vehicle (n = 11), WT Se (n = 10), 3xTg-AD vehicle (n = 9) and 3xTg-AD Se (n = 15). Statistical analysis was determined by one-way ANOVA followed by Bonferroni post hoc test. *P < 0.05, **P < 0.001, ***P < 0.001.
Figure 2
Figure 2
Selenium treatment reverses spatial learning and memory deficits in 3xTg-AD mice. (A) Spatial learning curves in the Morris water maze. The spatial training consisted of five-day training in the hidden platform version of the task. The performance of all groups improved significantly during the training days, although 3xTg-AD Veh mice show significantly longer latencies than the rest of groups. (B) Spatial reference memory in the MWM after treatment. Results represent the time spent in each quadrant in the post training probe trial. Compared to WT groups, 3xTg-AD Veh mice did not show a preference for the target quadrant (SE), whereas Se treatment enhances target quadrant preference in 3xTg-AD mice. (C) Swimming pathlengths during navigation in the probe trial. Heat plots of pathlengths of representative experimental mice during the probe trial. (D) Spatial navigation strategies of mice in the MWM. Top: Schematic representations of non-spatial and spatial navigation strategies in the MWM. Bottom: Effect of sodium selenate on non-spatial and spatial learning strategies in the MWM. Data represent mean ± s.e.m. Number of mice: WT vehicle (n = 11), WT Se (n = 10), 3xTg-AD Veh (n = 9) and 3xTg-AD Se (n = 14). Statistical analysis was determined by two-way ANOVA followed by Bonferroni post hoc test. *P < 0.05, ***P < 0.0001.
Figure 3
Figure 3
Amyloid pathology is not affected by selenium treatment in 3xTg-AD mice. (A) Cerebral amyloid pathology in 3xTg-AD mice at 13–14 months of age. Coronal brain sections of vehicle- (Veh) and Se-treated 3xTg-AD mice were stained with an Aβ antibody (6E10) to reveal the presence of intraneuronal Aβ (middle image) and amyloid plaques (right image) in the hippocampus. The middle and right images are magnified images of the left dashed areas (insets) corresponding to CA1 and subiculum subregions. Scale bars = 40 μm and 250 μm. (B) Quantification of amyloid pathology in the treated groups. Results include number of dense, sparse or total Aβ plaques and intraneuronal Aβ-positive neurons per section, for brain regions shown in (A) Data represent mean number ± s.e.m. n = 4–5 sections/mouse; n = 6–7 mice/group.
Figure 4
Figure 4
Tau pathology is reduced by selenium treatment in 3xTg-AD mice. (A) Cerebral tau pathology is present in the brain of 3xTg-AD at 13–14 months of age. Images show coronal brain sections of WT control (left) and vehicle- (middle) or Se (right)-treated 3xTg-AD mice stained with antibodies against phosphorylated tau (CP13: Ser202; PHF1: Ser396/Thr404) and conformational aggregated tau (MC1) found in AD. Upper three rows correspond to CA1 hippocampus and the bottom row images correspond to the temporal auditory cortex. Scale bar = 50 μm. Right: quantitative imaging analysis of phosphorylated or aggregated tau-positive neurons in vehicle- and Se-treated 3xTg-AD mice. Data represent number of tau-positive neurons per selected region ± s.e.m. n = 4–5 sections/mouse; n = 6–7 mice/group. (B,C) Biochemical analysis of tau and GSK3β in the hippocampus of WT and 3xTg-AD mice. Western blot images (B) and quantitative analysis (C) of phosphorylated tau (CP13, AT180 and PHF1), total tau (TG5 and 17025) and total and phosphorylated (Ser9) GSK3β. Original immunobloting scans and parts of the blots used for the figures are shown in Supplemental Information. Data represent relative levels of total and phosphorylated proteins as fold change ± s.e.m. n = 4–5 mice/group. Statistical analysis was determined by t-test (A) or two-way ANOVA followed by Bonferroni post hoc test (C). *P < 0.05, **P < 0.001 compared to 3xTg-AD Veh group.
Figure 5
Figure 5
Chronic selenium treatment reduces astrogliosis in the hippocampus of 3xTg-AD mice. (A) Immunohistological analysis of astrocytes in 3xTg-AD mice. Coronal brain sections stained with GFAP antibody to detect reactive astrocytes in the hippocampus of 14 month-old 3xTg-AD mice treated with vehicle (Veh) or Se for four months. Images show reduced GFAP staining in the CA1, CA3 and DG regions but not in the corpus callosum (CC) of 3xTg-AD mice treated chronically with Se (bottom) compared with vehicle (top). Scale bar = 50 μm. Data represent percentage of area stained with GFAP ± s.e.m. n = 4–5 mice/group. Statistical analysis was determined by t-test *P < 0.05 compared to 3xTg-AD Veh group. (B) Biochemical analysis of GFAP in the hippocampus of treated mice. Western blot images and quantification of GFAP levels in the hippocampus of WT and 3x-Tg-AD mice. Se reduces GFAP levels in the hippocampus of 3xTg-AD mice. Original immunobloting scans and parts of the blots used for the figures are shown in Supplemental Information. Data represent fold relative levels of GFAP ± s.e.m. n = 4–6 mice/group. Statistical analysis was determined by two-way ANOVA followed by Bonferroni post hoc test. **P < 0.001.
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