Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has important health and economic impacts in the elderly. Despite a better understanding of the molecular mechanisms leading to the appearance of major pathological hallmarks (senile plaques and neurofibrillary tangles), effective treatments are still lacking. Sporadic AD forms (98% of all cases) are multifactorial, and a panoply of risk factors have been identified. While the major risk factor is aging, growing evidence suggests that chronic stress or stress-related disorders increase the probability to develop AD. An early dysregulation of the hypothalamic-pituitary-adrenal axis (HPA axis or stress axis) has been observed in patients. The direct consequence of such perturbation is an oversecretion of glucocorticoids (GC) associated with an impairment of its receptors (glucocorticoid receptors, GR). These steroids hormones easily penetrate the brain and act in synergy with excitatory amino acids. An overexposure could be highly toxic in limbic structures (prefrontal cortex and hippocampus) and contribute in the cognitive decline occurring in AD. GC and GR dysregulations seem to be involved in lots of functions disturbed in AD and a vicious cycle appears, where AD induces HPA axis dysregulation, which in turn potentiates the pathology. This review article presents some preclinical and clinical studies focusing on the HPA axis hormones and their receptors to fight AD. Due to its primordial role in the maintenance of homeostasis, the HPA axis appears as a key-actor in the etiology of AD and a prime target to tackle AD by offering multiple angles of action.
Highlights
Reviewed by: Xiao-Xin Yan, Central South University, China Xudong Huang, Massachusetts General Hospital, Harvard Medical School, United States
Due to its primordial role in the maintenance of homeostasis, the HPA axis appears as a key-actor in the etiology of Alzheimer’s disease (AD) and a prime target to tackle AD by offering multiple angles of action
Growing evidence suggests that lifetime events such as chronic stress or stress-related disorders, like major depression disorder (MDD) or anxiety, may increase the probability to develop AD (Heininger, 2000; Blennow et al, 2006; Querfurth and LaFerla, 2010; Canet et al, 2019)
Summary
Sporadic Alzheimer’s disease (AD; 98% cases) is a progressive neurodegenerative pathology, and its complexity could be explained by a wide range of risk factors. Over-secretion associated with GC receptors (GR) signaling impairment These steroid hormones penetrate the brain tissue and act in synergy with excitatory amino acids. A vicious cycle between AD and the HPA axis seems to occur, where AD induces the dysregulation of the HPA axis, which in turn potentiates the pathology (Brureau et al, 2013; Pineau et al, 2016; Canet et al, 2019). This article reviews some preclinical and clinical studies focusing on the HPA axis hormones and receptors as potential targets for AD. This review intends to show that the HPA axis, due to its essential role in the maintenance of homeostasis, could be a key factor in the etiology of AD and a prime target to tackle AD by offering multiple druggable opportunities
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