The amyloidogenic potential and behavioral correlates of stress

Max Planck Institute of Psychiatry, Munich, Germany.
Molecular Psychiatry (Impact Factor: 14.5). 11/2007; 14(1):95-105. DOI: 10.1038/
Source: PubMed


Observations of elevated basal cortisol levels in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids (GC) may contribute to the development and/or maintenance of AD. Consistent with that hypothesis, we show that stress and GC provoke misprocessing of amyloid precursor peptide in the rat hippocampus and prefrontal cortex, resulting in increased levels of the peptide C-terminal fragment 99 (C99), whose further proteolytic cleavage results in the generation of amyloid-beta (Abeta). We also show that exogenous Abeta can reproduce the effects of stress and GC on C99 production and that a history of stress strikingly potentiates the C99-inducing effects of Abeta and GC. Previous work has indicated a role for Abeta in disruption of synaptic function and cognitive behaviors, and AD patients reportedly show signs of heightened anxiety. Here, behavioral analysis revealed that like stress and GC, Abeta administration causes spatial memory deficits that are exacerbated by stress and GC; additionally, Abeta, stress and GC induced a state of hyperanxiety. Given that the intrinsic properties of C99 and Abeta include neuroendangerment and behavioral impairment, our findings suggest a causal role for stress and GC in the etiopathogenesis of AD, and demonstrate that stressful life events and GC therapy can have a cumulative impact on the course of AD development and progression.

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Available from: Osborne F.X. Almeida, Dec 16, 2014
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    • "Aside from SI, other manners of chronic stresses, such as chronic immobilization stress (Jeong et al., 2006) and mild unpredictable chronic stress (Cuadrado-Tejedor et al., 2012), exacerbate amyloid production in transgenic mouse models of AD. Furthermore, unpredictable chronic stress can also alter APP metabolism toward the amyloidogenic pathway in normal, middle-aged rats (Catania et al., 2009). These studies highlight that various stresses, including SI, stimulate increases in the amyloidogenic pathway. "
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    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease characterized by gradual declines in social, cognitive, and emotional functions, leading to a loss of expected social behavior. Social isolation (SI) has been shown to have adverse effects on individual development, growth, as well as health and aging. Previous experiments have shown that SI causes an early onset of AD-like phenotypes in young APP/PS1 mice. However, the interactions between SI and AD still remain unknown. Seventeen-month old male APP/PS1 mice were either singly housed or continued group housing for 3 months. Then, AD-like pathophysiological changes were evaluated by using behavioral, biochemical and pathological analyses. Isolation housing further promoted cognitive dysfunction and Aβ plaque accumulation in the hippocampus of aged APP/PS1 mice, associated with increased γ-secretase and decreased neprilysin expression. Furthermore, exacerbated hippocampal atrophy, synapse and myelin associated protein loss, and glial neuroinflammatory reactions were observed in the hippocampus of isolated aged APP/PS1 mice. The results demonstrate that SI exacerbates AD-like pathophysiology in aged APP/PS1 mice, highlighting the potential role of group life for delaying or counteracting the AD process. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 01/2015; 18(7). DOI:10.1093/ijnp/pyu116 · 4.01 Impact Factor
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    • "Stress is a major risk-factor in many multifactorial diseases, such as cardiovascular diseases, psychiatric disorders like anxiety and depression, as well as neurodegenerative diseases such as Alzheimer's and Parkinson's disease (Lupien et al., 1994; Black and Garbutt, 2002; Esch et al., 2002; Bunker et al., 2003; De Kloet et al., 2005; Sotiropoulos et al., 2008; Catania et al., 2009). Still the etiology of these diseases remains elusive, as the interplay between genetic as well as environmental factors is difficult to disentangle. "
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    ABSTRACT: Stress and an altered stress response have been associated with many multifactorial diseases, such as psychiatric disorders or neurodegenerative diseases. As currently mouse mutants for each single gene are generated and phenotyped in a large-scale manner, it seems advisable also to test these mutants for alterations in their stress responses. Here we present the determinants of a robust and reliable non-invasive test for stress-responsivity in mice. Stress is applied through restraining the mice in tubes and recording behavior in the Open Field 20 min after cessation of the stress. Two hours, but not 15 or 50 min of restraint lead to a robust and reproducible increase in distance traveled and number of rearings during the first 5 min in the Open Field in C57BL/6 mice. This behavioral response is blocked by the corticosterone synthesis inhibitor metyrapone, but not by RU486 treatment, indicating that it depends on corticosteroid secretion, but is not mediated via the glucocorticoid receptor type II. We assumed that with a stress duration of 15 min one could detect hyper-responsivity, and with a stress duration of 2 h hypo-responsivity in mutant mouse lines. This was validated with two mutant lines known to show opposing effects on corticosterone secretion after stress exposure, corticotropin-releasing hormone (CRH) over-expressing mice and CRH receptor 1 knockout (KO) mice. Both lines showed the expected phenotype, i.e., increased stress responsivity in the CRH over-expressing mouse line (after 15 min restraint stress) and decreased stress responsivity in the CRHR1-KO mouse line (after 2 h of restraint stress). It is possible to repeat the acute stress test several times without the stressed animal adapting to it, and the behavioral response can be robustly evoked at different ages, in both sexes and in different mouse strains. Thus, locomotor and rearing behavior in the Open Field after an acute stress challenge can be used as reliable, non-invasive indicators of stress responsivity and corticosterone secretion in mice.
    Frontiers in Behavioral Neuroscience 04/2014; 8:125. DOI:10.3389/fnbeh.2014.00125 · 3.27 Impact Factor
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    • "It is possible that a decrease in brain metabolism due to a loss of SWS causes increases in A× † and ptau after sleep deprivation. However, a recent study showed that both stress and GC can drive APP metabolism toward amyloidogenesis and that a history of hypersecretion of GC, as result of chronic stress, biases APP processing toward the amyloidogenic pathway (Catania et al., 2009 "
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    ABSTRACT: Age-associated dysregulation of sleep can be worsened by Alzheimer's disease (AD). AD and sleep restriction both impair cognition, yet it is unknown if mild chronic sleep restriction modifies the proteopathic processes involved in AD. The goal of this work was to test the hypothesis that sleep restriction worsens memory impairments, and amyloid β-peptide (Aβ) and pTau accumulations in the brain in a mouse model of AD, with a focus on a role for circulating glucocorticoids (GC). Male 3xTgAD mice were subjected to sleep restriction (SR) for 6h/day for 6 weeks using the modified multiple platform technique, and behavioral (Morris water maze, fear conditioning, open field) and biochemical (immunoblot) outcomes were compared to mice undergoing daily cage transfers (large cage control; LCC) as well as control mice that remained in their home cage (control; CTL). At one week, both LCC and SR mice displayed significant elevations in plasma corticosterone compared to CTL (p<0.002). By four weeks, SR mice displayed a two-fold increase in circulating corticosterone levels compared to CTL. Behavioral data indicated deficits in contextual and cued memory in SR mice that were not present for LCC or CTL (p<0.04). Both Aβ and pTau levels increased in the cortex of SR mice compared to CTL and LCC; however these changes were not noted in the hippocampus. Significant positive correlations between cortical Aβ and pTau levels and circulating corticosterone indicate a potential role for GCs in mediating behavioral and biochemical changes observed after sleep restriction in a mouse model of AD.
    Brain research 07/2013; 1529. DOI:10.1016/j.brainres.2013.07.010 · 2.84 Impact Factor
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