Targeting Glucocorticoid Receptors: A New Avenue for Alzheimer’s Disease Therapy

Canet, Geoffrey; Chevallier, Nathalie; Perrier, Véronique; Desrumaux, Catherine; Givalois, Laurent

doi:10.1007/978-981-13-0944-1_15

Cited by 7 publications

(8 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sporadic Alzheimer’s disease (AD; 98% cases ) is a progressive neurodegenerative pathology, and its complexity could be explained by a wide range of risk factors. Growing evidence suggests that lifetime events such as chronic stress or stress-related disorders, like major depression disorder (MDD) or anxiety, may increase the probability to develop AD (Heininger, 2000; Blennow et al, 2006; Querfurth and LaFerla, 2010; Canet et al, 2019). In patients, an early dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis was observed (Hartmann et al, 1997; Csernansky et al, 2006).…”

Section: General Aspectsmentioning

confidence: 99%

“…Furthermore, GC and GR dysregulations are involved in lots of functions disturbed in AD: i.e., dysregulation of the amyloid precursor protein (APP) processing, Tau phosphorylation, neuroinflammation, oxidative stress and excitotoxicity (Sapolsky, 1996; McEwen, 2008; Bengoetxea et al, 2016). Thus, a vicious cycle between AD and the HPA axis seems to occur, where AD induces the dysregulation of the HPA axis, which in turn potentiates the pathology (Brureau et al, 2013; Pineau et al, 2016; Canet et al, 2019).…”

Section: General Aspectsmentioning

confidence: 99%

“…In limbic structures ( hippocampus, prefrontal cortex ), it was shown that GC overexposure induces hippocampal and cortical atrophy (McEwen, 2008) and amygdala hypertrophy (Vyas et al, 2003, 2004), that could be related to learning and memory deficits, emotional impairment, excitotoxicity, neuroinflammation and oxidative stress (Sapolsky, 1996; McEwen, 2008; Bengoetxea et al, 2016). In the AD context, high levels of GC, and the dysregulation of the HPA axis activity observed in patients (Hartmann et al, 1997; Swanwick et al, 1998), seems to be particularly involved in the induction of amyloidogenic pathway and the abnormal phosphorylation of Tau (Green et al, 2006; Pineau et al, 2016; Sotiropoulos and Sousa, 2016; Vyas et al, 2016; Canet et al, 2019). Thus, it appears that the rise of circulating GC increases AD pathology, resulting in a vicious cycle by which pathology induces HPA axis dysregulation, GC overexposure and GR signaling impairment, which in turn potentiates the pathology.…”

Section: The Hpa Axismentioning

confidence: 99%

See 2 more Smart Citations

Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets

Canet

Hernandez

Zussy

et al. 2019

Front. Aging Neurosci.

Self Cite

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has important health and economic impacts in the elderly. Despite a better understanding of the molecular mechanisms leading to the appearance of major pathological hallmarks (senile plaques and neurofibrillary tangles), effective treatments are still lacking. Sporadic AD forms (98% of all cases) are multifactorial, and a panoply of risk factors have been identified. While the major risk factor is aging, growing evidence suggests that chronic stress or stress-related disorders increase the probability to develop AD. An early dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis or stress axis) has been observed in patients. The direct consequence of such perturbation is an oversecretion of glucocorticoids (GC) associated with an impairment of its receptors (glucocorticoid receptors, GR). These steroids hormones easily penetrate the brain and act in synergy with excitatory amino acids. An overexposure could be highly toxic in limbic structures (prefrontal cortex and hippocampus) and contribute in the cognitive decline occurring in AD. GC and GR dysregulations seem to be involved in lots of functions disturbed in AD and a vicious cycle appears, where AD induces HPA axis dysregulation, which in turn potentiates the pathology. This review article presents some preclinical and clinical studies focusing on the HPA axis hormones and their receptors to fight AD. Due to its primordial role in the maintenance of homeostasis, the HPA axis appears as a key-actor in the etiology of AD and a prime target to tackle AD by offering multiple angles of action.

show abstract

Section: General Aspectsmentioning

confidence: 99%

Section: General Aspectsmentioning

confidence: 99%

Section: The Hpa Axismentioning

confidence: 99%

See 1 more Smart Citation

Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets

Canet

Hernandez

Zussy

et al. 2019

Front. Aging Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, it indicates a potential relation between cortisol levels and symptoms due to infectious disease. Further, there may even be a connection with Alzheimer disease, in which it has been noted that elevated levels of glucocorticoids and HPA axis dysfunction are consistently observed in patients [2]. Further correlations can be inferred from the undulation of fever characterizing disease such as brucella [5] and the rise and fall of CORT during the day and night [17] as well as respiratory systems during sleep [18,1].…”

Section: Introductionmentioning

confidence: 99%

Competitive Inhibition of Cortisol by Prostaglandins at the Ligand Binding Domain of Glucocorticoid Receptors

Schaper

2019

Preprint

View full text Add to dashboard Cite

Here, a pathway is shown for the first time indicating competitive inhibition of cortisol by prostaglandins at the critical ligand binding domain of glucocorticoid receptors. This is significant since these materials are widely distributed: glucocorticoid receptors, cortisol and prostaglandins are found in almost every cell and tissue in the human body. In this article, a cooperative relationship is shown between cortisol and prostaglandin results during normative homeostatic conditions, and thus indicates capability of localized control, which is instructive for understanding as well as diagnosis of deviations from optimal physiological function. Moreover, as glucocorticoid receptors are nominally driven through cortisol concentration, the hypothesis developed in this manuscript indicates that the introduction of exogenous sources of prostaglandins, as associated with bacterial infection for example, might trigger dysfunctional responses, including signs and symptoms of disease like fever. The results demonstrating this association of competitive inhibition of cortisol and prostaglandins include comparative molecular modeling analyzing hydrophobic, hydrogen bonding, electrostatic and topology considerations that indicate the similarity in chemical affinity of cortisol and prostaglandin in a preferred configuration at the site of the ligand binding domain of glucocorticoid receptors. The work is useful in understanding normative physiological function as well as for developing treatments during certain diseased states.

show abstract

“…It is noted that these symptoms of adrenal insufficiency are similar to that of an infection, which is even at times misdiagnosed [5] as such, since it is rather due to cortisol levels -thus, it indicates a potential relation between cortisol levels and symptoms due to infectious disease. Further, there may even be a connection with Alzheimer disease, in which it has been noted that elevated levels of glucocorticoids and HPA axis dysfunction are consistently observed in patients [2]. Further correlations can be inferred from the undulation of fever characterizing disease such as brucella [6] and the rise and fall of CORT during the day and night [23] as well as respiratory systems during sleep [24,1].…”

Section: Introductionmentioning

confidence: 99%

Identifying Integrative Molecular Pathways for Predictive Modeling of Infectious Disease

Schaper

2019

Preprint

View full text Add to dashboard Cite

The signs and symptoms of infectious disease are similar in presentation, such as fever and fatigue, but differ in magnitude, duration, and sequence. Although observable responses of dysfunction are well characterized, the integrative system mechanisms driving such trajectories are poorly known, even during normative circumstances. Here, molecular pathways are presented that enable predictive modeling of autonomic dysfunction due to infectious agents, and that illustrate a coordinating integration of body system dynamics. To arrive at this result, a molecular model is presented which shows, for the first time, that the hormone cortisol (CORT) and prostaglandin E2 (PGE2) have approximately equivalent chemical affinity, as indicated by the positioning of functional groups in hydrogen bonding and hydrophobicity, with the ligand binding domain of the glucocorticoid receptor (GR). A mathematical model is developed to predict that the signs and symptoms of illnesses are associated with the competitive inhibition at the GR of CORT and PGE2 within the hypothalamus that prevents normal gene expression during DNA transcription. To validate the pathways and model, a case study is presented to analyze the cause and presentation of fever and fatigue over multiple days due to the injection of a pneumococcal vaccine as influenced by physical activity. The research provides quantitative understanding of the root causes of signs and symptoms of infectious disease, which for example can offer a quantitative explanation of common symptomatic concerns of illness, such as fever, and can result in optimal drug treatment plans to minimize the effects of ailments. * charlesschaper@comcast.net Graphical Abstract

show abstract

Targeting Glucocorticoid Receptors: A New Avenue for Alzheimer’s Disease Therapy

Cited by 7 publications

References 99 publications

Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets

Is AD a Stress-Related Disorder? Focus on the HPA Axis and Its Promising Therapeutic Targets

Competitive Inhibition of Cortisol by Prostaglandins at the Ligand Binding Domain of Glucocorticoid Receptors

Identifying Integrative Molecular Pathways for Predictive Modeling of Infectious Disease

Contact Info

Product

Resources

About