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. 2013 Sep 5:1529:200-8.
doi: 10.1016/j.brainres.2013.07.010. Epub 2013 Jul 13.

Chronic mild sleep restriction accentuates contextual memory impairments, and accumulations of cortical Aβ and pTau in a mouse model of Alzheimer's disease

Sarah M Rothman  1 , Nathan Herdener, Kathryn A Frankola, Mohamed R Mughal, Mark P Mattson
Affiliations

Chronic mild sleep restriction accentuates contextual memory impairments, and accumulations of cortical Aβ and pTau in a mouse model of Alzheimer's disease

Sarah M Rothman et al. Brain Res. .

Abstract

Age-associated dysregulation of sleep can be worsened by Alzheimer's disease (AD). AD and sleep restriction both impair cognition, yet it is unknown if mild chronic sleep restriction modifies the proteopathic processes involved in AD. The goal of this work was to test the hypothesis that sleep restriction worsens memory impairments, and amyloid β-peptide (Aβ) and pTau accumulations in the brain in a mouse model of AD, with a focus on a role for circulating glucocorticoids (GC). Male 3xTgAD mice were subjected to sleep restriction (SR) for 6h/day for 6 weeks using the modified multiple platform technique, and behavioral (Morris water maze, fear conditioning, open field) and biochemical (immunoblot) outcomes were compared to mice undergoing daily cage transfers (large cage control; LCC) as well as control mice that remained in their home cage (control; CTL). At one week, both LCC and SR mice displayed significant elevations in plasma corticosterone compared to CTL (p<0.002). By four weeks, SR mice displayed a two-fold increase in circulating corticosterone levels compared to CTL. Behavioral data indicated deficits in contextual and cued memory in SR mice that were not present for LCC or CTL (p<0.04). Both Aβ and pTau levels increased in the cortex of SR mice compared to CTL and LCC; however these changes were not noted in the hippocampus. Significant positive correlations between cortical Aβ and pTau levels and circulating corticosterone indicate a potential role for GCs in mediating behavioral and biochemical changes observed after sleep restriction in a mouse model of AD.

Keywords: AD; Alzheimer′s disease; Amyloid; Aβ; CTL; Fear conditioning; GC; Glucocorticoids; LCC; MMP; MWM; Morris water maze; SR; Sleep restriction; amyloid beta; control; glucocorticoid; large cage control; modified multiple platform; pTau; phosphorylated tau; sleep restriction.

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Conflict of interest statement

Conflict of Interest

The authors report no conflicts of interest.

Figures

Figure 1
Figure 1
Blood plasma corticosterone in control (CTL), large cage control (LCC) and sleep restriction (SR) mice at 1 and 4 weeks after the start of the 6-week sleep restriction period.
Figure 2
Figure 2
Morris water maze results for all mice prior to sleep restriction (pre-SR) and after the 6 week sleep restriction period for control (post-SR CTL), large cage control (post-SR LCC) and sleep restricted mice (post-SR SR). The latency time to reach the hidden platform decreased over time for mice tested prior to the sleep restriction period (A). Mean swim speed was not significantly different between groups (B). At both the 4 and 24 hour probe test (C&D), mice tested prior to the sleep restriction period spent a significantly greater amount of time in the target quadrant (p<0.005) whereas after the 6 week sleep restriction period no groups, including control, displayed significant preference for the target quadrant, indicating a lack of short term memory retention.
Figure 3
Figure 3
Fear conditioning testing results for all mice after the 6 week sleep restriction period for control (post-SR CTL), large cage control (post-SR LCC) and sleep restricted mice (post-SR SR). On day 1, mice were exposed to tone-shock pairings (A). On day 2, mice were first tested in a contextual paradigm (B) followed by a cued paradigm (C).
Figure 4
Figure 4
After the 6 week sleep restriction period, no differences in the time spent in zone 1 (A) or the distance traveled in zone 1 (B) are observed between groups, implying that there are no differences in anxiety between the three groups (CTL, LCC, SR).
Figure 5
Figure 5
Western blot results from the cortex (A) and hippocampus (B) showing increases in expression of Aβ and ptau in large cage controls compared to control with a further increase in sleep restricted mice. Quantification of western blot results indicate that cortical Aβ expression increases in LCC and SR compared to CTL whereas ptau expression increases in SR (C). Hippocampal expression levels are largely unchanged between groups (D).
Figure 6
Figure 6
Correlations between circulating glucocorticoids and hippocampal and cortical expression of Aβ and ptau. Cortical expression of both Aβ and ptau are positively, significantly (pA–B). In the hippocampus, Aβ, but not ptau, is significantly correlated with circulating glucocorticoids (p=0.032; C–D). Circulating corticosterone was negatively and significantly (p=0.045) correlated with the percent time spent in the target quadrant during the 24 hour probe test (E).
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