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. 2013;8(4):e60437.
doi: 10.1371/journal.pone.0060437. Epub 2013 Apr 2.

Hunger in the absence of caloric restriction improves cognition and attenuates Alzheimer's disease pathology in a mouse model

Emily J Dhurandhar  1 , David B Allison, Thomas van Groen, Inga Kadish
Affiliations

Hunger in the absence of caloric restriction improves cognition and attenuates Alzheimer's disease pathology in a mouse model

Emily J Dhurandhar et al. PLoS One. 2013.

Abstract

It has been shown that caloric restriction (CR) delays aging and possibly delays the development of Alzheimer's disease (AD). We conjecture that the mechanism may involve interoceptive cues, rather than reduced energy intake per se. We determined that hunger alone, induced by a ghrelin agonist, reduces AD pathology and improves cognition in the APP-SwDI mouse model of AD. Long-term treatment with a ghrelin agonist was sufficient to improve the performance in the water maze. The treatment also reduced levels of amyloid beta (Aβ) and inflammation (microglial activation) at 6 months of age compared to the control group, similar to the effect of CR. Thus, a hunger-inducing drug attenuates AD pathology, in the absence of CR, and the neuroendocrine aspects of hunger also prevent age-related cognitive decline.

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Conflict of interest statement

Competing Interests: David B. Allison, Ph.D. has served as a consultant to Medifast. Dr. Allison has, anticipates, or has had financial interests with Vivus, Inc. and Kraft Foods, Paul Weiss, Wharton, and Garrison LLP; and Sage Publications. The ghrelin agonist was donated for the study by Eli Lilly. There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1
Figure 1. Left: Change in body weight over the treatment period.
Note that the control and LY animals gain equal weight during the treatment period, but the CR animals are significantly lighter; further, the CR mice had a significantly (p<0.001) lower fat mass compared to the other two groups. Right: Bar graph showing the percent of fat of the total body weight as determined by QMR. Note the reduced fat content of the CR mice.
Figure 2
Figure 2. Two bar graphs showing the time spent in different parts of the open field and elevated plus maze, respectively, of the three groups of mice.
No significant differences between the groups were present.
Figure 3
Figure 3. Two graphs showing the learning curves of the three groups of mice.
Left: The daily mean performance in the water maze. Right: the probe trial performance of the three groups of mice. Note that the improvement in trial time was significantly more in LY compared to the control (p = 0.023) and nearly significantly more in CR compared to the control (p = 0.08). Both LY and CR groups had a significant preference for the correct quadrant in the probe trial (p<0.05).
Figure 4
Figure 4. Two series of coronal sections of the dorsal hippocampus stained for Aβ.
A non-significant decrease in Aβ staining in stratum oriens and a significant reduction in Aβ staining in the dentate gyrus in both LY and CR mice compared to the control is shown. Lower panel, Aβ levels measured by ELISA. Insoluble Aβ-40 levels are significantly reduced in CR and LY groups compared to the control (*student's t-test p = 0.03 for both comparisons). Insoluble Aβ-42 levels are reduced in CR and LY compared to the control (**Tukey-Kramer HSD p = 0.02 for both comparisons). so - stratum oriens; sp - stratum pyramidale.
Figure 5
Figure 5. Six high-power photomicrographs of area CA1 of the dorsal hippocampus stained for Iba1 (top row) and GFAP (bottom row), respectively, of the three groups of mice.
cc - corpus callosum; so - stratum oriens; sp - stratum pyramidale. Note the significant (Tukey-Kramer HSD p = 0.0042) reduction in Iba1 staining in the CR and LY groups.
Figure 6
Figure 6. Four bar graphs showing the data from the inflammation measurements, top row, density measurements of Iba1 and GFAP staining in stratum oriens of the hippocampus, respectively (p = 0.0042 for Iba-1).
Bottom row, ELISA measurements of IL-6 and IL-10, respectively, levels in the hippocampal formation.
See this image and copyright information in PMC

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