부산대학교 도서관

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 (GC) consumption (corticosterone [CORT] in drinking water for 4 weeks). Then, to evaluate the consequences of chronic GC consumption on the onset of amyloid-[beta] (A[beta]) toxicity, animals chronically treated with GC were intracerebroventricularly injected with an oligomeric solution of A[beta][sub.25-35] (oA[beta]) (acute model of AD). We evaluated AD-related cognitive deficits and pathogenic mechanisms, with a special emphasis on neuroinflammatory markers. Results: Chronic CORT consumption caused the inhibition of the nonamyloidogenic pathways, the impairment of A[beta] clearance processes and the induction of amyloidogenic pathways in the hippocampus. The principal enzymes involved in glucocorticoid receptor activation and Tau phosphorylation were upregulated. Importantly, the AD-like phenotype triggered by chronic CORT was analogous to the one caused by oA[beta]. These molecular commonalities across models were independent from inflammation, as chronic CORT was immunosuppressive while oA[beta] was pro-inflammatory. When chronic CORT consumption anticipated the induction of the oA[beta] 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 CORT consumption as a main risk factor for AD and suggests that glucocorticoid-based therapies should be prescribed with caution in populations with AD risk. Keywords: Alzheimer's disease, Amyloid toxicity, Chronic glucocorticoids consumption, Neuroinflammation, Memory deficits
Author(s): Geoffrey Canet [a]; Charleine Zussy [a]; Célia Hernandez [a]; Nathalie Chevallier [a]; Nicola Marchi [b]; Catherine Desrumaux [a]; Laurent Givalois [a,c] Introduction Alzheimer's disease (AD) is the most common [...]