| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
|
FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online February 8, 2006 as doi:10.1096/fj.05-4265fje. |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Department of Pharmacology, College of Medicine, National Creative Research Initiative Centre for Alzheimer’s Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul, Korea;
Department of Neurosurgery, College of Medicine, Seoul National University, Seoul, Korea; and
Neurobiology Programme, The Babraham Institute, Babraham, Cambridge, UK
2Correspondence: Department of Pharmacology, College of Medicine, Seoul National University, 28 Yeongeon-dong, Jongno-gu, Seoul 110-799, Korea. E-mail: yhsuh{at}snu.ac.kr
SPECIFIC AIMS
To elucidate the effects of long-term stress on the onset and severity of cognitive deficits and pathological changes in APPV717I-CT100 transgenic mice (CT mice), we examined learning and memory ability using passive avoidance and social transfer of food preference (STFP) tests after chronic immobilization stress. The changes of extracellular amyloid deposits, intraneuronal amyloid ß peptide (Aß) and carboxyl-terminal fragments of APP (APP-CTFs) immunoreactivities, and neurodegeneration were also examined.
PRINCIPAL FINDINGS
1. Long-term stress accelerates behavioral impairments in APPV717I-CT100 transgenic mice
To examine the relationship between chronic stress and cognitive deficits in our AD mice model, learning and memory ability were assessed by using passive avoidance and STFP tests, after administering chronic immobilization stress for 8 months. APPV717I-CT100 mice were housed under stress (CT-S) or nonstress conditions (CT-C), as described above, from 3 months after birth. CT-S group animals exhibited significant memory deficits as compared with the CT-C group by passive avoidance test (Fig. 1
A) (n=5 per group, F2,12=10.26, *P<0.05, 1-way ANOVA).
|
In the STFP task, an olfactory memory task based on conspecifics as a source of food choice information, significant differences were found between CT-C and CT-S or CT-C old animals (Fig. 1B-D
). Olfactory-based behaviors can be confounded by general anosmia, and therefore, the task incorporated a basic olfactory discrimination test in addition to the olfactory memory test component. Mice were presented with a choice between familiar plain and novel aromatic powdered chows. Neophobia and olfactory functioning of APPV717I-CT100 transgenic mice were measured by determining plain food preference (Fig. 1B
). Plain food preference (%) was assessed by determining the ratio of plain food to total food consumed. In the present study, plain food consumption exceeded 50%, which is consistent with the typical neophobic response expected of rodents. These results suggest intact normal olfactory functioning in all experimental groups (n=5 per group, mean±SE) and that the only discriminating factor was a novel food flavoring.
We assessed short-term and long-term olfactory memory retrieval ability using the time difference cue test 1 h and 24 h after demonstrator-observer interaction. Cued food preference (%) was assessed by determining the percentage of cued food consumed vs. total food consumed. One hour after the demonstrator-observer interaction, significant group differences were observed in terms of cued food preference (%) (Fig. 1C
) (n=5 per group, F2,12=6.20, *P<0.05, 1-way ANOVA). Twenty-four hours after demonstrator-observer interactions, we found that cued food preference was significantly lower in the CT-S group than in the CT-C group (Fig. 1D
) (n=5 per group, F2,13=5.15, *P<0.05, 1-way ANOVA).
Plasma corticosterone concentrations were determined as a means of quantifying stress, and it was found that immobilization stress caused a significantly greater in blood corticosterone in the CT-S group than in the CT-C group (Fig. 1E
) (n=10 per group, F1,18=3.8, *P<0.05, Student’s t test).
2. Long-term stress increased extracellular amyloid plaques and intraneuronal Aß and APP-CTFs depositions in the hippocampus and cortex in APPV717I-CT100 transgenic mice
To investigate the possibility of links between memory impairment severity and amyloid deposition, we examined extracellular amyloid plaque load, and intraneuronal Aß and APP-CTFs depositions in 11-month-old APPV717I-CT100 transgenic mice (i.e., after behavioral tests) (Fig. 2
).
|
In the serial brain paraffin sections of the CT-C, CT-S, and CT-C old groups, extracellular Aß immunoreactive plaques and vascular deposits, as detected by 6E10 antibody, were highly stained in the hippocampal region (Fig. 2A-C
) and cortex (data not shown). However, extracellular Aß plaques in the hippocampal region of the CT-S group (Fig. 2B
) were significantly more numerous than in the CT-C group (Fig. 2A
).
Next, serial brain sections were also labeled with 6E10 and C9 antibodies conjugated with FITC (green) and Cy3 (red), respectively, and visualized by confocal microscopy. The intraneuronal immunoreactivities of Aß and APP-CTFs were highly elevated in the CT-S and the CT-C old group vs. the CT-C group, especially in the hippocampal CA3 region (Fig. 2J-L
).
Neuronal degenerative changes were observed by hematoxylin and eosin (H&E) staining. In serial brain sections, degenerating neurons (eosinophilic pyknotic neuron; Fig. 2M-R
) were observed in hippocampal C9 antibody positively stained regions (Fig. 2D-I
). Profoundly degenerated neurons were remarkably more increased in the hippocampal CA3 region of the CT-S group (Fig. 2Q
) than in the CT-C group (Fig. 2P
). However, no large difference was observed between the CT-S (Fig. 2N
) and CT-C (Fig. 2M
) groups in terms of the numbers of eosinophilic neurons in the hippocampal DG.
CONCLUSIONS AND SIGNIFICANCE
In the present study, we investigated the effects of chronic stress on the onset and severity of cognitive deficits and on pathological changes in APPV717I-CT100 transgenic mice. It was found that exposure of these mice to immobilization stress for 8 months (from ages 3 to 11 months) resulted in severe learning and memory impairments and that it increased extracellular amyloid plaque deposition, intraneuronal Aß, and APP-CTFs immunoreactivities, and neurodegeneration.
Passive avoidance test showed that latency times were not recovered in the CT-S group at 24 h after electric shock, suggesting that memory retrieval ability was more severely impaired by chronic stress. In the STFP tasks, 1 h and 24 h after demonstrator-observer interaction, short-term and long-term memory retrieval abilities were found to be more severely impaired in the CT-S group than in the CT-C group.
The amount of extracellular amyloid plaque was greater in the hippocampus and cortex of the CT-S group than in the CT-C group. In serial brain sections, APP-CTFs immunoreactive plaques largely overlapped with Aß immunoreactive plaques, indicating that most Aß immunoreactive plaques contained APP-CTFs.
The hippocampus is a target of stress hormones, and it is an especially plastic and vulnerable region of the brain. Chronic repeated psychosocial or restraint stress, or chronic treatment with corticosterone or adrenal steroids along with excitatory amino acids, especially causes apical dendrites atrophy in CA3 pyramidal neurons and specific cognitive deficits in spatial learning and memory, and alters mossy fiber synaptic terminal structure. However, dendritic atrophy was not observed in granule cells of the dentate gyrus, or in CA1 or CA2 pyramidal cells affected by these treatments.
In the present study, more significant increases of intraneuronal Aß and APP-CTFs immunoreactivities were observed in the CT-S group than in the CT-C group, especially in the CA3 region of the hippocampus. High levels of neurodegeneration were in the CA3 region of serial brain section, which suggests that increased intraneuronal Aß and APP-CTFs levels might be significantly correlated with neurodegeneration.
It appears that chronic stress increases extracellular plaque formation, the intraneuronal expressions of Aß and APP-CTFs, and neurodegeneration in the hippocampus, especially in the CA3 region of the hippocampus, a specific target region of stress hormones, by increasing the production and processing of APP-CTFs via hormonal stress mechanisms.
This study demonstrates that chronic stress accelerates cognitive impairments and increases extracellular amyloid deposition, intraneuronal Aß and APP-CTFs immunoreactivity, and neurodegeneration in an AD model, and suggests that disease onset, cognitive impairment, and neurodegeneration are correlated with depositions of Aß and APP-CTFs. Our study suggests that chronic stress is an important pathogenic factor in the onset and development of AD.
|
FOOTNOTES
1 These authors contributed equally to this work. 
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-4265fje;
This article has been cited by other articles:
|
|
 |
|
  R. A. Rissman, K.-F. Lee, W. Vale, and P. E. Sawchenko Corticotropin-Releasing Factor Receptors Differentially Regulate Stress-Induced Tau Phosphorylation J. Neurosci., June 13, 2007; 27(24): 6552 - 6562. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
