Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice - PubMed (original) (raw)

. 2007 May;205(1):166-76.

doi: 10.1016/j.expneurol.2007.01.037. Epub 2007 Feb 13.

Zhihong Guo, Veerendra Madala Halagappa, Michelle Pearson, Audrey J Gray, Yasuji Matsuoka, Martin Brown, Bronwen Martin, Titilola Iyun, Stuart Maudsley, Robert F Clark, Mark P Mattson

Affiliations

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Rhonda L Nelson et al. Exp Neurol. 2007 May.

Abstract

A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five-month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7-month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Abeta) and numbers of Abeta immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model suggests that such drugs administered prophylactically might retard the development of AD in humans.

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Figures

Figure 1

Figure 1

3xTgAD mice exhibit abnormalities in open field activity and passive avoidance tests, which are not ameliorated by paroxetine. A. Open field activities of male and female nontransgenic control mice and 3xTgAD mice. Values are the mean and SD (n = 5−10 mice). *p<0.01 compared to the corresponding value for nontransgenic mice. B. Transfer latency values in the passive avoidance test. Values are the mean and SD (n = 10). *p<0.05 compared to the corresponding value for nontransgenic mice.

Figure 1

Figure 1

3xTgAD mice exhibit abnormalities in open field activity and passive avoidance tests, which are not ameliorated by paroxetine. A. Open field activities of male and female nontransgenic control mice and 3xTgAD mice. Values are the mean and SD (n = 5−10 mice). *p<0.01 compared to the corresponding value for nontransgenic mice. B. Transfer latency values in the passive avoidance test. Values are the mean and SD (n = 10). *p<0.05 compared to the corresponding value for nontransgenic mice.

Figure 2

Figure 2

Paroxetine treatment ameliorates the impaired performance of 3xTgAD mice in the Morris spatial navigation task. A. Goal latencies (data for males and females combined). Values are the means and SD (n = 10). The performance of paroxetine-treated 3xTgAD mice was significantly different than that of vehicle-treated 3xTgAD mice (p<0.01). The performance of paroxetine-treated nontransgenic mice was significantly different than that of vehicle-treated nontransgenic mice (p<0.01). B. Results of probe trial (values for males and females combined). Values are the means and SD (n = 10).

Figure 2

Figure 2

Paroxetine treatment ameliorates the impaired performance of 3xTgAD mice in the Morris spatial navigation task. A. Goal latencies (data for males and females combined). Values are the means and SD (n = 10). The performance of paroxetine-treated 3xTgAD mice was significantly different than that of vehicle-treated 3xTgAD mice (p<0.01). The performance of paroxetine-treated nontransgenic mice was significantly different than that of vehicle-treated nontransgenic mice (p<0.01). B. Results of probe trial (values for males and females combined). Values are the means and SD (n = 10).

Figure 3

Figure 3

Aβ accumulation is reduced in paroxetine-treated 3xTgAD mice. A. Aβ1−40 levels in the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05 compared to the corresponding value for vehicle-treated mice. B. Micrographs showing Aβ immunoreactivity in the hippocampus and amygdala of 3xTgAD mice that had been treated with saline or paroxetine. C and D. Results of quantitative analysis of Aβ-positive neurons in region CA1 of the hippocampus (C) and the amygdala (D) of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5).

Figure 3

Figure 3

Aβ accumulation is reduced in paroxetine-treated 3xTgAD mice. A. Aβ1−40 levels in the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05 compared to the corresponding value for vehicle-treated mice. B. Micrographs showing Aβ immunoreactivity in the hippocampus and amygdala of 3xTgAD mice that had been treated with saline or paroxetine. C and D. Results of quantitative analysis of Aβ-positive neurons in region CA1 of the hippocampus (C) and the amygdala (D) of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5).

Figure 3

Figure 3

Aβ accumulation is reduced in paroxetine-treated 3xTgAD mice. A. Aβ1−40 levels in the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05 compared to the corresponding value for vehicle-treated mice. B. Micrographs showing Aβ immunoreactivity in the hippocampus and amygdala of 3xTgAD mice that had been treated with saline or paroxetine. C and D. Results of quantitative analysis of Aβ-positive neurons in region CA1 of the hippocampus (C) and the amygdala (D) of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5).

Figure 3

Figure 3

Aβ accumulation is reduced in paroxetine-treated 3xTgAD mice. A. Aβ1−40 levels in the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05 compared to the corresponding value for vehicle-treated mice. B. Micrographs showing Aβ immunoreactivity in the hippocampus and amygdala of 3xTgAD mice that had been treated with saline or paroxetine. C and D. Results of quantitative analysis of Aβ-positive neurons in region CA1 of the hippocampus (C) and the amygdala (D) of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5).

Figure 4

Figure 4

Paroxetine treatment attenuates tau pathology in male 3xTgAD mice. A. Micrographs showing tau immunoreactivity in the hippocampus of male and female 3xTgAD mice that had been treated with saline or paroxetine. B. Results of quantitative analysis of tau-positive neurons in region CA1 of the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05, **p<0.01 compared to the saline value. #p<0.05 compared to the male saline value. C. Micrographs showing tau immunoreactivity in the amygdala of 3xTgAD mice that had been treated with saline or paroxetine. D. Results of quantitative analysis of tau-positive neurons in the amygdala of the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05 compared to the saline value. #p<0.05 compared to the male saline value.

Figure 4

Figure 4

Paroxetine treatment attenuates tau pathology in male 3xTgAD mice. A. Micrographs showing tau immunoreactivity in the hippocampus of male and female 3xTgAD mice that had been treated with saline or paroxetine. B. Results of quantitative analysis of tau-positive neurons in region CA1 of the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05, **p<0.01 compared to the saline value. #p<0.05 compared to the male saline value. C. Micrographs showing tau immunoreactivity in the amygdala of 3xTgAD mice that had been treated with saline or paroxetine. D. Results of quantitative analysis of tau-positive neurons in the amygdala of the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05 compared to the saline value. #p<0.05 compared to the male saline value.

Figure 4

Figure 4

Paroxetine treatment attenuates tau pathology in male 3xTgAD mice. A. Micrographs showing tau immunoreactivity in the hippocampus of male and female 3xTgAD mice that had been treated with saline or paroxetine. B. Results of quantitative analysis of tau-positive neurons in region CA1 of the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05, **p<0.01 compared to the saline value. #p<0.05 compared to the male saline value. C. Micrographs showing tau immunoreactivity in the amygdala of 3xTgAD mice that had been treated with saline or paroxetine. D. Results of quantitative analysis of tau-positive neurons in the amygdala of the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05 compared to the saline value. #p<0.05 compared to the male saline value.

Figure 4

Figure 4

Paroxetine treatment attenuates tau pathology in male 3xTgAD mice. A. Micrographs showing tau immunoreactivity in the hippocampus of male and female 3xTgAD mice that had been treated with saline or paroxetine. B. Results of quantitative analysis of tau-positive neurons in region CA1 of the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05, **p<0.01 compared to the saline value. #p<0.05 compared to the male saline value. C. Micrographs showing tau immunoreactivity in the amygdala of 3xTgAD mice that had been treated with saline or paroxetine. D. Results of quantitative analysis of tau-positive neurons in the amygdala of the hippocampus of 3xTgAD mice that had been treated with saline or paroxetine. Values are the mean and SD (n = 5). *p<0.05 compared to the saline value. #p<0.05 compared to the male saline value.

Comment in

References

    1. Almaguer-Melian W, Cruz-Aguado R, Riva Cde L, Kendrick KM, Frey JU, Bergado J. Effect of LTP-reinforcing paradigms on neurotransmitter release in the dentate gyrus of young and aged rats. Biochem Biophys Res Commun. 2005;327:877–883. -PubMed
    1. Andersen SL, Teicher MH. Serotonin laterality in amygdala predicts performance in the elevated plus maze in rats. Neuroreport. 1999;10:3497–3500. -PubMed
    1. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992;42:631–639. -PubMed
    1. Ashe KH. Learning and memory in transgenic mice modeling Alzheimer's disease. Learn Mem. 2001;8:301–308. -PubMed
    1. Biegon A, Mathis C. Evaluation of [3H]paroxetine as an in vivo ligand for serotonin uptake sites: a quantitative autoradiographic study in the rat brain. Synapse. 1993;13:1–9. -PubMed

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