Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases?

Abstract

There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD). These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic–pituitary–adrenal (HPA)-axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioral deficits and/or mood disorders. Dysregulation of the HPA-axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, antidepressant drugs, such as the selective serotonin reuptake inhibitors have been shown to alter HPA-axis activity. In this review, we will summarize the current state of knowledge regarding HPA-axis pathology in Alzheimer’s, PD and HD, differentiating between prodromal and later stages of disease progression when evidence is available. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the preclinical evidence to better inform prospective, intervention studies.

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

“…The dysregulation in the negative corticosteroid feedback, as well as increased corticosteroid levels, is reported in AD patients and preclinical mouse models [18]. This is supported by the evidence that increased plasma levels have been reported in the early stages of AD patients [19, 20] and decreased sensitivity to low-dose dexamethasone suppression [6]. Similarly, patients with sporadic AD have increased plasma cortisol levels during the onset and later stages [21-23].…”

“…The central HPA axis is activated during the early stages of AD pathology, preceding cognitive impairment and behavioral symptoms [15]. In humans, the early accumulation of the pathological forms of Aβ is likely to contribute to overall dysregulation of the HPA axis [6]. The HPA axis dysfunction in AD is reflected by elevated basal levels of circulating cortisol in human patients and corticosterone in mouse models [15].…”

Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis

“…For decades, clinicians have reported severe changes in metabolism, mood, and behavior in HD patients, symptoms that often precede more obvious effects of the disease on motor function and implicate serotonergic systems (Du and Pang, 2015; Folstein and Folstein, 1983; Wang et al, 2014). In mammalian models of HD, dysfunction of serotonergic signaling pathways has been reported, with both tryptophan hydroxylase activity and 5-HT levels diminishing (Mattson et al, 2004; Pang et al, 2009).…”

Neuroendocrine and neurotrophic signaling in Huntington’s disease: Implications for pathogenic mechanisms and treatment strategies

“…Loss of this neuronal population is thought to contribute to circadian rhythm disturbances, HPA-axis dysfunction and subsequent alterations in cortisol release (24). Moreover, HPA-axis dysregulation has been proposed as a contributing factor to co-morbid depression in neurodegenerative diseases, including HD (for a comprehensive review, see 86).…”