Chronic glucocorticoids consumption triggers and worsens experimental Alzheimer’s disease-like pathology by detrimental immune-modulations

Abstract

Introduction: Among the risk factors identified in the sporadic forms of Alzheimer’s disease (AD), environmental and lifestyle elements are of growing interest. Clinical observations suggest that stressful events can anticipate AD onset, while stress-related disorders can promote AD. Here, we tested the hypothesis that a chronic treatment with glucocorticoids, is sufficient to trigger or exacerbate AD molecular hallmarks. Methods: We first validated a rat model of experimental chronic glucocorticoids consumption (corticosterone in drinking water for 4 weeks). Then, to evaluate the consequences of chronic glucocorticoids consumption on the onset of amyloid-β (Aβ) toxicity, animals chronically treated with glucocorticoids were intracerebroventricularly injected with an oligomeric solution of Aβ25-35 (oAβ) (acute model of AD). We evaluated AD-related cognitive deficits and pathogenic mechanisms, with a special emphasis on neuroinflammatory markers. Results: Chronic corticosterone consumption caused the inhibition of the non-amyloidogenic pathways, the impairment of Aβ clearance processes and the induction of amyloidogenic pathways in the hippocampus. The principal enzymes involved in glucocorticoid receptor (GR) activation and Tau phosphorylation were upregulated. Importantly, the AD-like phenotype triggered by chronic corticosterone was analogous to the one caused by oAβ. These molecular commonalities across models were independent from inflammation, as chronic corticosterone was immunosuppressive while oAβ was pro-inflammatory. When chronic corticosterone consumption anticipated the induction of the oAβ pathology, we found a potentiation of neuroinflammatory processes associated with an exacerbation of synaptic and memory deficits but also an aggravation of AD-related hallmarks. Discussion/Conclusion: This study unravels new functional outcomes identifying chronic corticosterone consumption as a main risk factor for AD and suggests that glucocorticoid-based therapies should be prescribed with caution in populations with AD risk.