Chronic stress induced cognitive impairment in APP/PS-1 double transgenic mouse model of Alzheimer's disease

Abstract

Objective  To observe the effect of chronic unpredictable mild stress (CUMS) on the cognitive function and brain morphological changes in APP/PS-1 mice, one of the genetic mouse models of Alzheimer's disease (AD), and to investigate the possible role of environmental factors in genetic mouse model of AD. Methods  There were 22-week-old wild-type C57BL/6 male mice (control group, N = 15) and APP/PS-1 double transgenic male mice [N = 27: AD group (N = 13) and AD + CUMS group (N = 14)] tested in this study. Morris water maze test was used to evaluate spatial learning and memory of the mice. Amyloid deposition in the hippocampus was determined by Congo red staining. The ultrastructure of neurons in hippocampal CA1 region was observed by transmission electron microscope (TEM).  Results  Compared with control group, AD + CUMS group had significantly longer fifth-day escape latency [(33.14 ± 14.37) s vs (21.22 ± 12.16) s; t = -2.701, P = 0.045], and significantly shortened time spent in platform quadrant [(9.74±1.35) s vs (15.02 ± 1.33) s; t = 2.639, P = 0.012] in Morris water maze test. Compared with AD group, the percentage of amyloid plaque area in hippocampal area was increased in AD + CUMS group [(0.59 ± 0.03)% vs (0.04 ± 0.03)%; t = -2.900, P = 0.005]. The ultrastructure of hippocampal neurons in AD group was slightly damaged: cellular membrane was intact; cell matrix was uniform; intracelluar lipofuscin could be seen; the structure of nucleus and nuclear membrane had no obvious changes; mild fusion of cristae and membrane was seen in mitochondria; Golgi apparatus was partially indistinct; endoplasmic reticulum was mildly expanded. The ultrastructure of hippocampal neurons in AD + CUMS group was obviously damaged, including blurred cell membrane, reduced low-density and high-density granules in cytoplasm, uneven cell matrix, reduced number of organelles, lipofuscin and autophagosome deposition, obvious condensation of chromatin distributing over the fringe of nuclei, blurred nuclear membrane, serious fusion of mitochondrial cristae and membrane, and obviously decreased free ribosome in cytoplasm.  Conclusions  Chronic unpredictable mild stress plays an inducing role in cognitive impairment of AD mice, aggravating the pathological changes of hippocampal neurons.

DOI: 10.3969/j.issn.1672-6731.2015.08.006