Abstract
Clinical studies have found that some Alzheimer’s disease (AD) patients suffer from Cushing’s syndrome (CS). CS is caused by the long-term release of excess glucocorticoids (GCs) from the adrenal gland, which in turn, impair brain function and induce dementia. Thus, we investigated the mechanism of the effect of corticosterone (CORT) on the development and progression of AD in a preclinical model. Specifically, the plasma CORT levels of 9-month-old APP/PS1 Tg mice were abnormally increased, suggesting an association between GCs and AD. Long-term administration of CORT accelerated cognitive dysfunction by increasing the production and deposition of β-amyloid (Aβ). The mechanism of action of CORT treatment involved stimulation of the expression of BACE-1 and presenilin (PS) 1 in in vitro and in vivo. This observation was confirmed in mice with adrenalectomy (ADX), which had lower levels of GCs. Moreover, the glucocorticoid receptor (GR) mediated the effects of CORT on the stimulation of the expression of BACE-1 and PS1 via the PKA and CREB pathways in neuroblastoma N2a cells. In addition to these mechanisms, CORT can induce a cognitive decline in APP/PS1 Tg mice by inducing apoptosis and decreasing the differentiation of neurons.
Highlights
Clinical studies have found that Alzheimer’s disease (AD) patients usually suffer from corticosteronism, which is characterized by the secretion of high levels of glucocorticoids (GCs) from the adrenal cortex (Guldiken and Guldiken, 2008; Haraguchi et al, 2016)
To detect whether the basic level of GCs is changed in AD animal models and whether the metabolic pathway of amyloid can change the production of GCs, the plasma CORT level of amyloid precursor protein (APP)/PS1 Tg mice of various ages was detected
According to the data provided by Jackson Laboratory, APP/PS1 Tg mice express chimeric Mo/HuAPP695swe and mutant PS1-dE9 genes, Aβ is deposited in the brain of 6-month-old mice
Summary
Clinical studies have found that Alzheimer’s disease (AD) patients usually suffer from corticosteronism, which is characterized by the secretion of high levels of glucocorticoids (GCs) from the adrenal cortex (Guldiken and Guldiken, 2008; Haraguchi et al, 2016). When the cortisol dropped to the basal level, the size of the hippocampus will be enlarged accompanied by improving the learning ability (Starkman et al, 2001, 2003). Chronic high levels of GC lead to a decrease in the volume of the hippocampus, which results in impairing cognitive ability (Starkman et al, 1992; Sheline et al, 1996; Bettio et al, 2017). Patients with high levels of GC show long-term
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