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
    • "In various preclinical AD models, stress worsens deficits in hippocampus-dependent spatial learning (Catania et al, 2009; Cuadrado-Tejedor et al, 2012; Dong et al, 2004; Jeong et al, 2006; Srivareerat et al, 2009; Tran et al, 2010). These deleterious effects are in part caused by an accelerated accumulation of Ab under stressing conditions (Catania et al, 2009; Cuadrado-Tejedor et al, 2012; Dong et al, 2004; Green et al, 2006; Jeong et al, 2006; Srivareerat "
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    ABSTRACT: The early phase of Alzheimer's disease (AD) is characterized by hippocampus-dependent memory deficits and impaired synaptic plasticity. Increasing evidence suggests that stress and dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, marked by elevated circulating glucocorticoids, are risk factors for AD onset. How these changes contribute to early hippocampal dysfunction remains unclear. Using an elaborated version of the object recognition task, we carefully monitored alterations in key components of episodic memory, the first type of memory altered in AD patients, in early symptomatic Tg2576 AD mice. We also combined biochemical and ex vivo electrophysiological analyses to reveal novel cellular and molecular dysregulations underpinning the onset of the pathology. We show that HPA axis circadian rhythm and feedback mechanisms, as well as episodic memory, are compromised in this early symptomatic phase, reminiscent of human AD pathology. The cognitive decline could be rescued by sub-chronic in vivo treatment with RU486, a glucocorticoid receptor antagonist. These observed phenotypes were paralleled by a specific enhancement of N-Methyl-D-aspartic acid receptor (NMDAR)-dependent LTD in CA1 pyramidal neurons, while LTP and metabotropic glutamate receptor-dependent LTD remain unchanged. NMDAR transmission was also enhanced. Finally, we show that, as for the behavioral deficit, RU486 treatment rescues this abnormal synaptic phenotype. These preclinical results define glucocorticoid signaling as a contributing factor to both episodic memory loss and early synaptic failure in this AD mouse model, and suggest that glucocorticoid receptor targeting strategies could be beneficial to delay AD onset.Neuropsychopharmacology accepted article preview online, 27 January 2015. doi:10.1038/npp.2015.25.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2015; 40(7). DOI:10.1038/npp.2015.25 · 7.05 Impact Factor
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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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