Central Role of Glucocorticoid Receptors in Alzheimer’s Disease and Depression

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

Brain Vitamin E Deficiency During Development Is Associated With Increased Glutamate Levels and Anxiety in Adult Mice

Vitamin E, the most important lipophilic radical scavenging antioxidant in vivo, has a pivotal role in brain. In an earlier study, we observed that adult mice with a defect in the gene encoding plasma phospholipid transfer protein (PLTP) display a moderate reduction in cerebral vitamin E levels, and exacerbated anxiety despite normal locomotion and memory functions. Here we sought to determine whether dietary vitamin E supplementation can modulate neurotransmitter levels and alleviate the increased anxiety phenotype of PLTP-deficient (PLTP−/−) mice. To address this question, a vitamin E-enriched diet was used, and two complementary approches were implemented: (i) “early supplementation”: neurotransmitter levels and anxiety were assessed in 6 months old PLTP−/− mice born from vitamin E-supplemented parents; and (ii) “late supplementation”: neurotransmitter levels and anxiety were assessed in 6 months old PLTP−/− mice fed a vitamin E-enriched diet from weaning. Our results show for the first time that an inadequate supply of vitamin E during development, due to moderate maternal vitamin E deficiency, is associated with reduced brain vitamin E levels at birth and irreversible alterations in brain glutamate levels. They also suggest this deficiency is associated with increased anxiety at adulthood. Thus, the present study leads to conclude on the importance of the micronutrient vitamin E during pregnancy

HIV Neuroinfection and Alzheimer’s Disease: Similarities and Potential Links?

Environmental factors such as chemicals, stress and pathogens are now widely believed to play important roles in the onset of some brain diseases, as they are associated with neuronal impairment and acute or chronic inflammation. Alzheimer’s disease (AD) is characterized by progressive synaptic dysfunction and neurodegeneration that ultimately lead to dementia. Neuroinflammation also plays a prominent role in AD and possible links to viruses have been proposed. In particular, the human immunodeficiency virus (HIV) can pass the blood-brain barrier and cause neuronal dysfunction leading to cognitive dysfunctions called HIV-associated neurocognitive disorders (HAND). Similarities between HAND and HIV exist as numerous factors involved in AD such as members of the amyloid and Tau pathways, as well as stress-related pathways or blood brain barrier (BBB) regulators, seem to be modulated by HIV brain infection, leading to the accumulation of amyloid plaques or neurofibrillary tangles (NFT) in some patients. Here, we summarize findings regarding how HIV and some of its proteins such as Tat and gp120 modulate signaling and cellular pathways also impaired in AD, suggesting similarities and convergences of these two pathologies

Role of Glucocorticoids in the Modulation of Corticotropin-Releasing Hormone mRNA Level by the Endogenous Benzodiazepine Receptor Ligand Octadecaneuropeptide in Rat Brain

International audienceWe have recently demonstrated that the endozepine octadecaneuropeptide (ODN) exerts an inhibitory influence on corticotropin-releasing hormone (CRH) mRNA expression. The effect is mediated by GABAA receptors and is reversed by adrenalectomy. In order to investigate the involvement of peripheral steroids and more particularly of glucocorticoids in the ODN modulation of CRH mRNA expression, we have evaluated, in adrenalectomized and castrated male rats (ADX/CX), the effect of dexamethasone (DEX) pretreatment on CRH mRNA expression induced by central injection of ODN. Variations in the CRH mRNA expression in the hypothalamic paraventricular nucleus have been studied using quantitative in situ hybridization. The intracerebroventricular injection of ODN (4 microg/kg), as previously reported, induced a significant inhibition of CRH mRNA expression in sham-operated rats (-33%). This inhibition was reversed in ADX/CX male rats (+65% vs. sham vehicle-injected rats and +20% vs. ADX/CX vehicle-injected rats). Pretreatment with DEX (5 mg/kg) during 4 days induced in ADX/CX rats a decrease of 22% (vs. ADX/CX vehicle-injected rats) in the CRH mRNA signal, which became comparable to that observed in sham vehicle-injected rats. Pretreatment of ADX/CX animals with DEX prevented the ODN-induced increase in CRH mRNA expression, inducing rather a 16 and 30% inhibition when compared to vehicle- and ODN-injected ADX/CX rats, respectively. Moreover the CRH mRNA levels observed in ODN-injected ADC/CX rats were higher than those observed in sham vehicle- and sham ODN-injected rats (+16% vs. sham vehicle-injected rats and +63% vs. sham ODN-injected rats). These results indicate that dexamethasone treatment in ADX/CX rats can restore mRNA levels to those observed in sham-operated animals but not the inhibiting effect induced by ODN. Together with previous findings, these results suggest that adrenal and/or gonadal factor(s) other than glucocorticoids are involved in ODN modulation of the HPA axis

Dehydroepiandrosterone administration reverses the inhibitory influence of aging on gonadotrophin-releasing hormone gene expression in the male and female rat brain

International audienceDehydroepiandrosterone (DHEA) has been shown to exert a beneficial influence on some aging-associated deficits in rodents. It is well documented that in the rat, aging is associated with a decline in reproductive functions. In order to evaluate the effect of DHEA on GnRH gene expression in aged animals, we have studied the effect of 2.5-d administration of DHEA to young (50-54 d of age) and aged (18 mo of age) rats of both sexes. In the young males, DHEA induced an 18% reduction in the hybridization signal. In the aged animals, the mRNA levels were 10% lower than those observed in the young rats. DHEA completely restored the mRNA levels when compared to those detected in young male animals. In the young female, DHEA produced a 11% increase in GnRH mRNA, whereas, in the aged animals, hybridization signal was decreased by 28%. DHEA administration to aged females induced a 33% increase in the amount of mRNA, thus completely reversing the influence of aging. These results indicate that the decrease in GnRH gene expression which is likely involved in the loss of reproductive functions in aged rats can be totally reversed by a short term administration of DHEA which restored the GnRH neuronal activity. They also suggest that DHEA might play a role in the prevention and/or improvement of some deficits associated with aging through stimulation of GnRH biosynthesis

Caractérisation des effets de l'injection intracérébroventriculaire du peptide b-amyloïde [25-35] chez le rat mâle adulte (impact sur un système de neuroprotection endogène)

La maladie d'Alzheimer (MA) est une pathologie neurodégénérative caractérisée par la présence de plaques séniles majoritairement composées par la protéine b-amyloïde (Ab). Afin de caractériser les effets de la toxicité amyloïde, nous avons évalué l'impact au cours du temps d'une injection intracérébroventriculaire (icv) du peptide Ab25-35 agrégé sur des paramètres comportementaux, physiologiques et biochimiques chez le rat et sur un système neuroprotecteur endogène, le BDNF. Nous avons caractérisé 1, 2, 3 et 6 sem après l'injection icv d'Ab25-35, les effets sur la mémoire à court- et long-terme, sur les niveaux dans l'amygdale, le cortex frontal, l'hippocampe et l'hypothalamus du stress oxydant, des processus apoptotiques et du BDNF ainsi que ces récepteurs (TrkB et p75). Chez ces animaux, des études immunohistologiques sont également réalisées sur le système BDNF, la neuroinflammation, la neurogénèse et la perte cellulaire hippocampique. Cette étude montre que l'injection d'Ab25-35 induit des déficits mnésiques, un stress oxydant, de la mitochondrie et du réticulum endoplasmique et des processus apoptotiques. L'Ab25-35 a un impact sur le système cholinergique, l'intégrité hippocampique, la neurogénèse et la neuroinflammation. Les taux de corticostérone et le système BDNF sont également modifiés. L'injection icv d'Ab25-35 induit les signes neuropathologiques majeurs de la MA chez le rat et valide ce modèle d'injection comme un bon modèle non-transgénique de la MA. De plus, il semble qu'une partie des effets observés pourraient être le résultat d'une dérégulation du système BDNF dans certaines régions du cerveau.Alzheimer's disease is a neurodegenerative pathology characterized by the presence of senile plaques. The major component of senile plaques is an amyloid-ß protein (Ab). In this study, we assessed the time-course effects and regional changes observed after a single intracerebroventricular (icv) injection of aggregated Ab fragment [25-35] (Ab25-35; 10 g/rat), on physiological parameters (body weight, general activity and body temperature), behavioral responses (spatial short- and long-term memories), stress parameters (BDNF and CORT levels, oxidative, inflammation, neuroprotection, cellular) and on histological parameters (neuroinflammation, acetylcholine systems, hippocampus integrity, BDNF system). We shown that a single icv injection of Ab25-35 has a significant impact on short- and long-term memories, HPA axis activity, oxidative stress, brain level of a neuroprotective agent (BDNF) and its receptors (TrkB and p75), ER and mitochondrial stress, apoptotic processes, astrogliosis and microgliosis, cholinergic systems, hippocampus integrity and hippocampal neurogenesis. This study allows to realize the parallel existing between the effects induced by Ab25-35 icv injection and numerous relevant signs of the pathology observed in patients. It seems that effects observed could be due to differential regulation of BDNF system on cerebral regionsMONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Central nitric oxide regulation of the hypothalamic-pituitary-adrenocortical axis in adult male rats.

International audienceThe presence of nitric oxide (NO) synthase (NOS) in hypothalamic structures which control the activity of the pituitary-adrenocortical axis suggests that NO might be involved in the central regulation of ACTH secretion. We have studied the involvement of NO in the activity of the hypopothalamic-pituitary-adrenocortical (HPA) axis in intact and adrenalectomized rats. The acute effects (4 h) of two NOS inhibitors (HP-228 and NMMA), injected into the left lateral cerebral ventricle of freely moving male rats, on hypothalamic CRH and pituitary proopiomelacortin (POMC) mRNA levels as well as ACTH plasma levels were evaluated. In intact rats, HP-228, but not NMMA, induced an increase in CRH mRNA levels, while in adrenalectomized animals, both NOS inhibitors were effective in increasing CRH mRNA. In intact and adrenalectomized rats, both NOS inhibitors induced an increase in anterior pituitary POMC mRNA levels. Plasma ACTH levels were significantly elevated from 30 min to 2 h following the administration of either HP-228 or NMMA. In adrenalectomized animals, both NOS inhibitors produced a much striking increase of plasma ACTH levels which were still significantly increased at the longest time-interval studied. These results suggest that the central NO system exerts a tonic negative influence on the activity of the HPA axis in the presence or absence of circulating glucocorticoids

Effet de l'injection intracérébroventriculaire du peptide Ab 25-35 chez le rat mâle adulte au cours du temps (toxicité amyloïde et implication dans la dérégulation de l axe Hypothalamo-hypophyso-surrénalien)

La maladie d'Alzheimer (MA) est une maladie neurodégénérative caractérisée par la présence d'enchevêtrements neurofibrillaires et de plaques séniles. Le composant majoritaire des plaques séniles est le peptide amyloïde Ab.Dans une première partie de cette thèse, l'objectif a été de caractériser la toxicité du peptide Ab25-35 après son injection au niveau des ventricules latéraux chez le rat au cours du temps. Nous avons ainsi pu démontrer, entre autre, qu'une seule injection, engendre des déficits mnésiques à court et à long terme qui persistent six semaines après l'injection. Nous avons également montré, entre autre, une astrogliose, une microgliose, une élévation du stress oxydant, ainsi que des phénomènes apoptotiques dans les différentes structures cérébrales étudiées. Le deuxième objectif de cette thèse a été de caractériser le rôle du peptide Ab25-35 dans la régulation de l'axe hypothalamo-hypophyso-surrénalien (HPA) au cours du temps. Dans un premier temps nous avons démontré une hyperactivité de l'axe, qui se caractérise par une modification de l'expression des hormones et une modification d'expression et de localisation des récepteurs aux glucocorticoïdes (GC). Nous avons montré que l'injection d'Ab25-35 induisait un comportement anxieux. Néanmoins la fonctionnalité du rétrocontrôle négatif des GC reste intacte. Alors que l'injection de l'Ab25-35 modifie la réponse de l'axe HPA à un stress. Nos résultats, dans un modèle pathomimétique, de la MA, montrent que la toxicité amyloïde modifie la fonctionnalité et la réactivité de l'axe HPA, ce qui pourrait participer à la pathophysiologie de la MA.Alzheimer's disease (AD) is characterized by neurofibrillary tangles and seniles plaques. The major component of senile plaques is the amyloid-b peptide (Ab). In a first part of this thesis, we characterized the time course toxicity effect of the Ab25-35 intracerebroventricular (icv) injection in the rat brain. We particulary demonstrated, that only one injection induced memories impairments at short and long term which persisted six weeks after the icv injection. We also shown, a sustain astrogliosis and microgliosis, oxidative stress, apoptotics processes in the differents brain structure of interest.In a second part of this thesis, we characterized the time course impact of Ab25-35 on hypothalamo-pituitary-adrenal axis during the time. First, we demonstrated an the hyperactivity of the axis, which is characterized by modifications of hormonal concentration associated with modification of the expression and localization of glucocorticoids (GC) receptors. We also demonstrated Ab25-35 an anxious behavioural in animals. Nevertheless, the functionality of negative feedback is not modified. However, Ab25-35 injection modify the HPA axis reactivity after acute stress. In conclusions, we shown, in a pathomimetic model of AD that the Ab25-35 toxicity modifes the reactivity and the functionality of HPA axis, that could be partly involved in the pathophysiology of AD.MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Involvement of neurosteroids in the effect of the endogenous benzodiazepine receptor ligand octadecaneuropeptide (ODN) on gonadotropin-releasing hormone gene expression in rat brain.

International audienceWe have recently demonstrated that different activators of the GABAA receptor complex including reduced progesterone metabolites and the endozepine octodecaneuropeptide (ODN) exert an inhibitory influence on GnRH gene expression. In order to investigate the possible involvement of neurosteroids, especially progesterone metabolites in the effect of ODN, we have evaluated in adrenalectomized and castrated male rats the influence of pretreatment with an inhibitor of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) trilostane (TRIL) and an inhibitor of 5 alpha-reductase MK-906 on GnRH mRNA levels in ODN-treated rats. TRIL completely prevented the inhibitory influence of ODN on GnRH mRNA. It was also found that the inhibitor of 3 beta-HSD as well as pregnenolone sulfate (PREG-S), which has been shown to be increased following TRIL treatment, could induce an increase in GnRH mRNA. MK-906 could also completely reverse the negative influence of ODN. When administered alone, this antagonist of 5 alpha-reductase induced an increase in GnRH mRNA. These results clearly indicate that the inhibition of two key enzymes for the synthesis of reduced progesterone metabolites can completely prevent the inhibitory influence of the endozepine ODN, suggesting that the effect of this endogenous ligand might be completely or partially mediated by an activation of the synthesis of active progesterone metabolites. On the other hand, it remains possible that, as a consequence of enzymatic inhibition, an increase in some precursors known as antagonists of GABAA may play a role in the prevention of the ODN effect by the two enzyme antagonists

Differential involvement of adrenal and gonadal steroids in anterior and intermediate pituitary pro-opiomelanocortin mRNA expression induced by the endogenous benzodiazepine, octadecaneuropeptide, in adult male rats.

International audienceThe involvement of the endogenous benzodiazepine, octadecaneuropeptide (ODN), in the regulation of proopiomelanocortin (POMC) mRNA expression at the pituitary level, and the influence of adrenal and gonadal steroids, have been studied using a quantitative in situ hybridization technique. I.c.v. injection of ODN (4 micrograms/kg) in sham-operated rats induced a 17 and 7% decrease in the POMC mRNA expression in anterior and intermediate pituitary lobes respectively. To determine the reciprocal involvement of adrenal and gonadal steroids in this regulation, animals were adrenalectomized and/or castrated. Adrenalectomy significantly increased POMC mRNA expression by 48% at the anterior pituitary level, but induced a 10% decrease of hybridization signal at the intermediate pituitary lobe (vs control sham-operated). Adrenal ablation reversed the effect induced by ODN and increased POMC mRNA expression at the anterior and intermediate pituitary levels by 60 and 10% respectively, compared with control sham-operated. By contrast, castration, which produced a decrease in POMC mRNA in the anterior pituitary and an increase in the intermediate lobe, did not modify the negative influence of ODN observed in sham-operated animals. When rats were adrenalectomized and castrated, the adrenalectomy influence was predominant at the anterior pituitary level, since ODN increased significantly the hybridization signal (+68% vs control sham-operated), while the castration influence was predominant at the intermediate pituitary level, since ODN induced an 11% decrease in POMC mRNA signal compared with control sham-operated. These studies indicate that, in vivo, the decrease in POMC mRNA expression in the anterior and intermediate pituitary induced by an endogenous benzodiazepine is differently modulated by adrenal and gonadal steroids, with a predominant influence of adrenal steroids at the anterior pituitary level and gonadal steroids at the intermediate pituitary level