Behavioral Stress Fails to Accelerate the Onset and Progression of Plaque Pathology in the Brain of a Mouse Model of Alzheimer's Disease

<div><p>Conflicting findings exist regarding the link between environmental factors and development of Alzheimer's disease (AD) in a variety of transgenic mouse models of AD. In the present study, we investigated the effect of behavioral stress on the onset and progression of Aβ pathology in the brains of TgCRND8 mice, a transgenic mouse model of AD. One group of TgCRND8 mice was subjected to restraint stress starting at 1 month of age until they were 3 months old, while restraint stress in the second group started at 4 months of age until they were 6 months old. After 2 months of treatment, no differences in the soluble, formic acid extracted, or histologically detected Aβ deposition in the cortical and hippocampal levels were found between non-stressed and stressed mice. These results showed that restraint stress alone failed to aggravate amyloid pathology when initiated either before or after the age of amyloid plaque deposition in TgCRND8 mice, suggesting that if stress aggravated AD phenotype, it may not be via an amyloid-related mechanism in the TgCRND8 mice. These findings are indicative that plaque load per se may not be used as a significant criterion for evaluating the effect of stress on AD patients.</p></div

Restraint stress activated hypothalamic neurons in TgCRND8 mice.

<p>A–D: Cross sections of the brains stained with c-fos immunohistochemical staining in PVN (A and C) and SON (B and D) of TgCRND8 mice at the age of 4 months undergone restraint stress (A and B) and non-stress treatment (C and D). E: Quantitative analysis of number of c-fos immunoreactive nuclei in SON of stressed and non-stressed TgCRND8 mice. * indicates statistical differences when compared with their age-matched non-stressed controls at <i>p</i><0.01. Scale bar = 150 µm.</p

Cross sections of the brains were stained with Thioflavin S staining in TgCRND8 mice at the age of 1 (A), 3 (B) and 6 (C) months.

<p>Scale bar = 100 µm.</p

Effects of restraint stress on Aβ1-40 or Aβ1-42 levels in TgCRND8 mice.

<p>ELISA was used to measure Aβ levels in hippocampal tissues after completion of the restraint stress procedure. The data were expressed as means ± SEM. Restraint stress had no significant effect on Aβ levels in either soluble fraction or nonsoluble fraction.</p

The number of Thioflavin S-positive plaques/section in the brains of TgCRND8 mice at the age of 1, 3 or 6 month-old.

<p>The number of Thioflavin S-positive plaques/section in the brains of TgCRND8 mice at the age of 1, 3 or 6 month-old.</p

Plasma corticosterone levels in the stressed TgCRND8 mice increased compared with that in their non-stressed controls at the age of 3 and 6 month-old.

<p>* indicates statistical differences when compared with their age-matched non-stressed controls at <i>p</i><0.01.</p

Restraint stress did not influence cortical and hippocampal amyloid plaque loads.

<p>A–D, Cross sections of the brains stained with bam-10 immunohistochemical staining in TgCRND8 mice at the age of 3 (A, B) or 6 months (C, D) under stress (A, C) and non-stress (B, D). E–F, Quantitative analysis of Aβ deposit burden in either cortex or hippocampus in TgCRND8 mice at the age of 3 (E) or 6 months (F) under stress or non-stress. Scale bar = 300 µm.</p