title: Subchronic glucocorticoid receptor inhibition rescues early episodic memory and synaptic plasticity deficits in a mouse model of Alzheimer's disease.
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 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.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lanté
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France.
authors.forename: Magda
authors.initials: M
authors.lastname: Chafai
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France.
authors.forename: Elisabeth Fabienne
authors.initials: EF
authors.lastname: Raymond
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France.
authors.forename: Ana Rita Salgueiro
authors.initials: AR
authors.lastname: Pereira
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Mouska
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France.
authors.forename: Scherazad
authors.initials: S
authors.lastname: Kootar
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Barik
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Bethus
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Marie
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D003907:Dexamethasone / Q000627:therapeutic use; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005938:Glucocorticoids / Q000097:blood / Q000627:therapeutic use; D006624:Hippocampus / Q000473:pathology; D006727:Hormone Antagonists / Q000627:therapeutic use; D006801:Humans; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology*; D061212:Memory, Episodic; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015735:Mifepristone / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D011810:Quinoxalines / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D018691:Excitatory Amino Acid Antagonists; D005938:Glucocorticoids; D006727:Hormone Antagonists; D011810:Quinoxalines; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; C056723:FG 9041; C056639:2-amino-5-phosphopentanoic acid; D003907:Dexamethasone; D014633:Valine