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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    • "Thus, oxidative stress-mediated hippocampal neuronal degeneration underscores memory impairment due to chronic stress. However, there are suggestions that compounds with neuroprotective property may be of benefits in chronic stress-induced cognitive deficits and other neuropsychiatric disorders (Panossian, 2013; Rothman and Mattson 2010;Catania et al., 2009;Balkan et al., 2001;Patil et al., 2006). Therefore, it may be concluded that neuroprotection offered by MJ may also contribute significantly to its adaptogenic-like property in reversing memory deficits induced by UCMS in mice. "
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    ABSTRACT: This study was undertaken to evaluate the adaptogenic-like activity of methyl jasmonate (MJ) in mice exposed to unpredictable chronic mild stress (UCMS). Male Swiss mice were treated with MJ (25-100mg/kg, i.p.) 30min before exposure to UCMS daily for 14 days prior to testing for memory and anxiety. Thereafter, the blood glucose and serum corticosterone levels were estimated using glucometer and ELISA. The brain concentrations of malondialdehyde (MDA) and glutathione (GSH) were estimated using spectrophotometer. Brain histology and the population of healthy neurons in the hippocampal regions were also assessed. MJ reversed anxiety and memory impairment produced by UCMS, which suggest adaptogenic-like property. The reduction in the weight of adrenal gland and liver in MJ-treated groups further indicates adaptogenic activity. It further decreases the blood glucose and serum corticosterone levels in UCMS-mice. Also, MJ decreases the concentrations of MDA and elevated the levels of GSH in the brain of mice exposed to UCMS. Brain histology revealed that MJ attenuated UCMS-induced degeneration and death of neuronal cells in the pyramidal layer of the cornu ammonis 3 (CA3) and the sub-granular zone of the dentate gyrus of the hippocampus. Moreover, MJ decreased the population of dead neuronal cells of the pyramidal layer of the CA3 and the sub-granular zone of the dentate gyrus of the UCMS-mice, which suggests neuroprotection. Taken together, these findings suggest that MJ demonstrated adaptogenic-like activity in mice; which might be related to modulation of serum corticosterone levels, inhibition of oxidative stress and neuroprotection.
    Full-text · Article · Nov 2015 · Brain research bulletin
    • "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.
    No preview · Article · Jan 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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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.
    Full-text · Article · Jan 2015 · The International Journal of Neuropsychopharmacology
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