title: Deregulation of hypothalamic-pituitary-adrenal axis functions in an Alzheimer's disease rat model.
abstract: Elevated cortisol evidence in Alzheimer's disease (AD) patients prompted the hypothesis that stress and glucocorticoids are involved in the development and/or maintenance of AD. We investigated the hypothalamic-pituitary-adrenal (HPA) axis activity, functionality, and reactivity for up to 6 weeks after an intracerebroventricular injection of amyloid-β(25-35) peptide (Aβ(25-35)) in rat, a validated acute model of AD. Aβ(25-35) induces memory impairment, alteration of anxiety responses, HPA axis hyperactivity, and glucocorticoid (GR) and mineralocorticoid (MR) receptor increases in brain regions related to HPA axis functions. GR are progressively translocated in neurons nucleus, while membrane version of MR is evidenced in all structures considered. The MR/GR ratio was modified in all structures considered. Aβ(25-35) induces a subtle disturbance in the feedback of the HPA axis, without modifying its functionality. The reactivity alteration is long-lasting, suggesting that amyloid toxicity affects the HPA axis adaptive response to stress. These findings are evidence of progressive HPA axis deregulation after Aβ(25-35), which is associated with an imbalance of MR/GR ratio and a disruption of the glucocorticoid receptors nucleocytoplasmic shuttling, and suggest that elevated glucocorticoids observed in AD could be first a consequence of amyloid toxicity.
authors.affiliation: Molecular Mechanisms in Neurodegenerative Dementia Laboratory, Inserm U710, Montpellier, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brureau
authors.forename: Charleine
authors.initials: C
authors.lastname: Zussy
authors.forename: Brice
authors.initials: B
authors.lastname: Delair
authors.forename: Charline
authors.initials: C
authors.lastname: Ogier
authors.forename: Guy
authors.initials: G
authors.lastname: Ixart
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
authors.forename: Laurent
authors.initials: L
authors.lastname: Givalois
mesh_terms: D000544:Alzheimer Disease; D000818:Animals; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D008297:Male; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid