Glucocorticoids increase impairments in learning and memory due to elevated amyloid precursor protein expression and neuronal apoptosis in 12-month old mice

Li, Weizu; Yao, Yiming; Zhang, Wen; Yin, Yong; Wu, Guo-Cui; Gong, Huiyu

doi:10.1016/j.ejphar.2009.11.045

Cited by 53 publications

(42 citation statements)

References 35 publications

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“…It will be important, in future studies, to identify the interplay between this previously identified pathological mechanism and the novel CORT-dependent mechanism we report now. These two cellular pathways are certainly not mutually exclusive and could in fact be intimately linked as a study in AD and several studies in immunology research suggest (Distelhorst, 2002;Li et al, 2010a).…”

Section: Discussionmentioning

confidence: 99%

Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

Lanté

Chafaï

Raymond

et al. 2015

Neuropsychopharmacol

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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 the 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 subchronic 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, whereas 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.

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Section: Discussionmentioning

confidence: 99%

Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

Lanté

Chafaï

Raymond

et al. 2015

Neuropsychopharmacol

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“…Furthermore, by interfering with GR functions, infl ammatory cytokines attenuate the negative feedback inhibition of glucocorticoid release mediated by GRs [47] ; excessive secretion of glucocorticoids ultimately results in hyperglucocorticoidemia, which reduces the BDNF levels in the brain, leading to apoptosis or degeneration of neurons [48] .…”

Section: The Infl Ammatory Cytokine Hypothesis Of Depression and Relamentioning

confidence: 99%

“…The increased secretion of CRH, ACTH, and glucocorticoids has been reported in the cerebrospinal fluid of patients with depression [69] . High concentrations of glucocorticoids can have long-term adverse effects, which include: (1) imbalance of negative feedback in the HPA axis, including downregulation of negative feedback and dysfunction of GRs, disinhibition in the dexamethasone suppression test, and high concentrations of glucocorticoids in the blood; (2) excessive activation of GRs in its target cells in the CNS leads to neuronal apoptosis and degeneration [48] which is explained by the attenuation of BDNF expression and proliferation [70,71] . In addition, the increased glucocorticoid levels enhance the expression of 5-HT transporters in the hippocampus, the frontal cortex, the amygdala, the dorsal raphe nucleus, and other brain regions in a GR-dependent manner, resulting in reduced 5-HT in the synaptic cleft and aggravation of depressive symptoms [72] .…”

Section: The Hypothalamus-pituitary-adrenal Axis Hyperactivity Hypothmentioning

confidence: 99%

New hypothesis and treatment targets of depression: an integrated view of key findings

2015

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Major depressive disorder (MDD) is a common and devastating psychiatric disorder characterized by persistent low mood, cognitive disorder, and impaired social function. Despite its complex mechanisms, increasing evidence has identified the involvement of neurotrophic factors, inflammatory cytokines, the hypothalamuspituitary-adrenal axis, and glutamate receptors in the pathophysiology of this illness. The present review synthesizes recent research achievements to defi ne the network between different hypotheses of MDD and to understand which part is most pivotal for its pathogenesis. By integrating MDD-related signal pathways, we highlight brain-derived neurotrophic factor (BDNF) dysfunction and increased apoptosis as the fi nal common cascades, and new therapeutic strategies aiming to enhance BDNF function have been shown to exert a rapid and effective antidepressant action.

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“…Noteworthy, glucocorticoids could potentiate A␤-induced learning and memory impairment and pathological damage in CA1 field of hippocampus in SpragueDawley rats [13]. Furthermore, we also found that glucocorticoids can increase impairments in learning and memory due to elevated amyloid-␤ protein precursor (A␤PP) expression and neuronal apoptosis in 12-month-old mice [14].…”

Section: Introductionmentioning

confidence: 71%

The Synergistic Roles of the Chronic Prenatal and Offspring Stress Exposures in Impairing Offspring Learning and Memory

Tang

Cheng

Wang

et al. 2016

JAD

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Abstract. In Alzheimer's disease (AD), extensive experimental studies have demonstrated a negative impact of chronic stress during various stages of life (including prenatal phase) on some aspects of AD pathology. Nevertheless, presently, few studies have been involved in the learning and memory impairments, as well as neuropathology elicited by the chronic prenatal stress (CPS) and the chronic offspring stress (COS) exposures simultaneously, particularly for the adult male APPswe/PS1dE9 murine offspring. Therefore, the aim of the present study was to investigate the influence of CPS on learning and memory impairments induced by COS in 6-month-old male APPswe/PS1dE9 offspring mice and the related mechanism. Our study firstly demonstrates that 14-day exposure to CPS could exacerbate the learning and memory impairments, as well as neuropathological damages in the CA3 regions of the hippocampus and cortex neurons, which is induced by the 28-day exposure to COS in 6-month-old male APPswe/PS1dE9 offspring mice. In addition, CPS could potentiate the production of A␤PP, A␤ 42, and corticosterone in 6-month-old male APPswe/PS1dE9 offspring that also suffer COS. In conclusion, our novel findings strongly implicate the synergistic roles of the CPS and COS exposures in impairing offspring learning and memory. Moreover, CPS potentiating the production of A␤ 42 might be mediated by glucocorticoids through increasing the expression of APP and BACE1 gene.

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Glucocorticoids increase impairments in learning and memory due to elevated amyloid precursor protein expression and neuronal apoptosis in 12-month old mice

Cited by 53 publications

References 35 publications

Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

New hypothesis and treatment targets of depression: an integrated view of key findings

The Synergistic Roles of the Chronic Prenatal and Offspring Stress Exposures in Impairing Offspring Learning and Memory

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