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.

Superiority of the Triple-Acting 5-HT6R/5-HT3R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT6R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats

“…Multiple pieces of evidence support the correlation between Cdk5 overactivity and the pathogenesis of AD. Consistent with previous data, 41,42 the icv injection of oAβ 25−35 induced an increase in Cdk5 expression (Figure 8A,B,F,G) and an elevated conversion of p35 to p25 (Figure 8A,C,F,H), ultimately leading to Cdk5 overactivation. Our findings demonstrate that both PZ-1922 and intepirdine effectively blocked Cdk5 activation in the hippocampus, regardless of the preventive or curative approach (Figures 8, S9, and S12).…”

“…As previously reported, , behavioral changes induced by oAβ 25–35 were accompanied by alterations in hippocampal synapses, as evidenced by a decrease in PSD-95 and SYN levels (Figure D–F,J–L). When administered as a curative or preventive treatment, PZ-1922 effectively reversed and prevented both postsynaptic and presynaptic deficits (Figure D,E,J,K).…”

“…Since astrocyte activation and recruitment of microglia contribute to the neuroinflammatory processes, we next assessed the hippocampal GFAP and Iba1. As previously reported, ,, we observed a transient activation of astrocytes only 1 week after the icv injection of oAβ 25–35 , as demonstrated by the increased level of GFAP in the preventive approach (Figures A,D,F,I, S10A,B, S13A,B). This was followed by a sustained recruitment of microglial cells (Figures A,E,F,J, S10C,D, and S13C,D).…”

Seizure activity triggers tau hyperphosphorylation and amyloidogenic pathways

“…For brain tissue harvesting (quantitative polymerase chain reaction [qPCR]), deeply anesthetized (ketamine/xylazine) mice were perfused by intracardiac cold saline. For Western blot analysis of phosphorylated brain proteins and blood collection, samples were processed as previously described 16,17 . When needed (e.g., failure of EEG implant, suffering), euthanasia was performed using CO2 inhalation.…”

“…For Western blot analysis of phosphorylated brain proteins and blood collection, samples were processed as previously described. 16,17 When needed (e.g., failure of EEG implant, suffering), euthanasia was performed using CO2 inhalation.…”