Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease

Abstract

Abbreviations: Aβ, amyloid-β peptide; ADAM10, A disintegrin and metalloproteinase domain-containing protein 10 (α-secretase); APP, amyloid precursor AbstractDysregulation of the hypothalamic-pituitary-adrenal (HPA) axis occurs early in Alzheimer's disease (AD), associated with elevated circulating glucocorticoids (GC) and glucocorticoid receptors (GR) signaling impairment. However, the precise role of GR in the pathophysiology of AD remains unclear. Using an acute model of AD induced by the intracerebroventricular injection of amyloid-β oligomers (oAβ), we analyzed cellular and behavioral hallmarks of AD, GR signaling pathways, processing of amyloid precursor protein, and enzymes involved in Tau phosphorylation.We focused on the prefrontal cortex (PFC), particularly rich in GR, early altered in AD and involved in HPA axis control and cognitive functions. We found that oAβ impaired cognitive and emotional behaviors, increased plasma GC levels, synaptic deficits, apoptosis and neuroinflammatory processes. Moreover, oAβ potentiated the amyloidogenic pathway and enzymes involved both in Tau hyperphosphorylation and GR activation. Treatment with a selective GR modulator (sGRm) normalized plasma GC levels and all behavioral and biochemical parameters analyzed. GR seems to occupy a central position in the pathophysiology of AD. Deregulation of | 1153 CANET ET Al.

Seizure activity triggers tau hyperphosphorylation and amyloidogenic pathways

“…27 We focused on the equilibrium between proinflammatory glia activation and cytokine/chemokine release and the anti-inflammatory activity of the glucocorticoid receptor (GR). 11,20,23 In the MTLE model, we report a stable increase of GFAP and Iba1 (Figure S1D,E and Figure 6A,B) with no participation of an endogenous anti-inflammatory response, as indicated by the decreased GR phosphorylation (pGR/GR) long-term in the ipsilateral epileptogenic and contralateral seizure propagating hippocampi (Figure S1F and Figure 6C), and no variation of corticosterone levels as we previously reported. 11 By contrast, after a generalized SE episode, the increase in GFAP, Iba1 (Figure S2D,E), and transcript levels of soluble cytokines and chemokines (IL-1β, TNFα, CCL12; Table S3) was transient (72 h to 1 week).…”

“…As previously proposed for other neurological diseases, 47 epileptogenesis and recurrent seizures could induce a prolonged suprathreshold activation of the GR system, resulting in its desensitization over time. This pattern shares elements of similarity with the J20 mice (Figures 6 and 7A) and a model of amyloid toxicity induced by the intracerebroventricular injection of an oligomeric solution of Aβ 21,23,48 . Within this framework, targeting the GR system could represent a strategy to reestablish the homeostatic control of inflammation, limiting neurodegenerative trajectories during seizures 49,50 …”

“…Finally, we asked how inflammation associates with the outlined pathological patterns in the two seizure models 27 . We focused on the equilibrium between proinflammatory glia activation and cytokine/chemokine release and the anti‐inflammatory activity of the glucocorticoid receptor (GR) 11,20,23 . In the MTLE model, we report a stable increase of GFAP and Iba1 (Figure and Figure 6A,B) with no participation of an endogenous anti‐inflammatory response, as indicated by the decreased GR phosphorylation (pGR/GR) long‐term in the ipsilateral epileptogenic and contralateral seizure propagating hippocampi (Figure and Figure 6C), and no variation of corticosterone levels as we previously reported 11 .…”

“…This pattern shares elements of similarity with the J20 mice (Figures 6 and 7A) and a model of amyloid toxicity induced by the intracerebroventricular injection of an oligomeric solution of Aβ. 21,23,48 Within this framework, targeting the GR system could represent a strategy to reestablish the homeostatic control of inflammation, limiting neurodegenerative trajectories during seizures. 49,50…”

Mineralocorticoid receptor antagonist‐mediated cognitive improvement in a mouse model of Alzheimer's type: possible involvement of BDNF‐H2S‐Nrf2 signaling

“…The affinity of glucocorticoid receptors for glucocorticoids is approximately one‐tenth in comparison to mineralocorticoid receptors for glucocorticoids [39,40]. Studies have also shown that the persistent increase in glucocorticoid levels during chronic stress may facilitate the onset and progression of Alzheimer’s disease [41] and accordingly glucocorticoid receptor antagonists have shown the improvement in cognitive functions [42,43,44,45].…”