Central role of glucocorticoid receptors in Alzheimer's disease and depression

Canet, Geoffrey; Chevallier, Nathalie; Zussy, Charleine; Desrumaux, Catherine; Givalois, Laurent

doi:10.3389/fnins.2018.00739

Cited by 106Stress Responses and CortisolAlzheimer's disease research and treatmentsAdrenal Hormones and Disorders

Central role of glucocorticoid receptors in Alzheimer's disease and depression

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Canet, Geoffrey, Chevallier, Nathalie, Zussy, Charleine, Desrumaux, Catherine, Givalois, Laurent·2018·Frontiers in Neuroscience

DOI 10.3389/fnins.2018.00739PMC PMC6232776

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Abstract

Alzheimer's disease (AD) is the principal neurodegenerative pathology in the world displaying negative impacts on both the health and social ability of patients and inducing considerable economic costs. In the case of sporadic forms of AD (more than 95% of patients), even if mechanisms are unknown, some risk factors were identified. The principal risk is aging, but there is growing evidence that lifetime events like chronic stress or stress-related disorders may increase the probability to develop AD. This mini-review reinforces the rationale to consider major depressive disorder (MDD) as an important risk factor to develop AD and points the central role played by the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids (GC) and their receptors (GR) in the etiology of MDD and AD. Several strategies directly targeting GR were tested to neutralize the HPA axis dysregulation and GC overproduction. Given the ubiquitous expression of GR, antagonists have many undesired side effects, limiting their therapeutic potential. However, a new class of molecules was developed, highly selective and acting as modulators. They present the advantage to selectively abrogate pathogenic GR-dependent processes, while retaining beneficial aspects of GR signaling. In fact, these "selective GR modulators" induce a receptor conformation that allows activation of only a subset of downstream signaling pathways, explaining their capacity to combine agonistic and antagonistic properties. Thus, targeting GR with selective modulators, alone or in association with current strategies, becomes particularly attractive and relevant to develop novel preventive and/or therapeutic strategies to tackle disorders associated with a dysregulation of the HPA axis.

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In the World Mental Health (WMH) surveys, median within-country depression age-of-onset was 26 (interquartile range 17-37) years of age in high-income countries and 24 (17-35) years in low- and middle-income countries.
“In the World Mental Health (WMH) surveys, median within-country depression AOO was 26 (interquartile range 17-37) years of age in high-income countries and 24 (17-35) years in low- and middle-income countries.”
From Time for united action on depression: a Lancet–World Psychiatric Association Commission (2022) · cites this paper as [163]
There was a meaningful secondary peak for onset of depression late in life.
“There was also a meaningful secondary peak for onset late in life. 163”
From Time for united action on depression: a Lancet–World Psychiatric Association Commission (2022) · cites this paper as [163]

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Authors: Canet, G., Chevallier, N., Zussy, C., Desrumaux, C., & Givalois, L.
Affiliations: Inserm (FR)
Corresponding author: Givalois, Laurent
ORCID: Canet, Geoffrey
Zussy, Charleine
Desrumaux, Catherine
Givalois, Laurent
Venue: Frontiers in Neuroscience
Publisher: Frontiers Media SA
Published: 2018-10-16
Volume: 12
Pages: 739-739
ISSN: 1662-453X (ISSN-L)
DOI: 10.3389/fnins.2018.00739
PMC: PMC6232776
OpenAlex: W2897424830
Cited by: 106
References: 120
Citations by year: 2026: 7 · 2025: 5 · 2024: 13 · 2023: 21 · 2022: 17 · 2021: 15 · 2020: 16 · 2019: 12
FWCI: 1.21
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: Frontiers in Neuroscience (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
HAL (submittedVersion, other-oa)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders: Association France Alzheimer (SM2016#1512)
Agence Nationale de la Recherche (ANR-11-LABEX-0021-LipSTIC)
Université de Montpellier (CBS2 PhD program)
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords: glucocorticoid receptor, Alzheimer's disease, major depressive disorder, hypothalamic-pituitary-adrenal axis, glucocorticoids, chronic stress, stress-related disorders, selective glucocorticoid receptor modulators, neurodegeneration, risk factors

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