Chronic stress and Alzheimer's disease: the interplay between the hypothalamic–pituitary–adrenal axis, genetics and microglia

Abstract

Chronic psychosocial stress is increasingly being recognised as a risk factor for sporadic Alzheimer's disease (AD). The hypothalamic-pituitary-adrenal axis (HPA axis) is the major stress response pathway in the body and tightly regulates the production of cortisol, a glucocorticoid hormone. Dysregulation of the HPA axis and increased levels of cortisol are commonly found in AD patients and make a major contribution to the disease process. The underlying mechanisms remain poorly understood. In addition, within the general population there are interindividual differences in sensitivities to glucocorticoid and stress responses, which are thought to be due to a combination of genetic and environmental factors. These differences could ultimately impact an individuals' risk of AD. The purpose of this review is first to summarise the literature describing environmental and genetic factors that can impact an individual's HPA axis reactivity and function and ultimately AD risk. Secondly, we propose a mechanism by which genetic factors that influence HPA axis reactivity may also impact inflammation, a key driver of neurodegeneration. We hypothesize that these factors can mediate glucocorticoid priming of the immune cells of the brain, microglia, to become pro-inflammatory and promote a neurotoxic environment resulting in neurodegeneration. Understanding the underlying molecular mechanisms and identifying these genetic factors has implications for evaluating stress-related risk/progression to neurodegeneration, informing the success of interventions based on stress management and potential risks associated with the common use of glucocorticoids.

Identification of hyper‐ramified microglia in the CA1 region of the mouse hippocampus potentially associated with stress resilience

“…Microglia, the resident immune cells of the brain, are involved in responses to social stress (Milligan Armstrong et al, 2021). For instance, exposure to restraint stress triggers the release of glucocorticoids, which promote the proliferation of microglia through glutamate receptor activation in the hippocampus (Nair & Bonneau, 2006).…”

Alzheimer’s Disease and Impaired Bone Microarchitecture, Regeneration and Potential Genetic Links

“…Chronic psychosocial stress is increasingly being recognized as a risk factor for sporadic AD [ 67 ]. The hypothalamic–pituitary–adrenal axis (HPA axis) is the major stress response pathway in the body and tightly regulates the production of cortisol [ 68 ], a glucocorticoid hormone.…”

Neuropathological Aspects of SARS-CoV-2 Infection: Significance for Both Alzheimer’s and Parkinson’s Disease

“…Furthermore, given that infection with a wide variety of pathogens is suspected to be a risk factor for the onset of AD ( Seaks and Wilcock, 2020 ; Vigasova et al, 2021 ), an increased risk of developing AD and cognitive impairment in susceptible populations after SARS-CoV-2 infection would also be expected. Moreover, these patients often face social stigma and mental stress, which can further aggravate neuroinflammatory processes and result in psychiatric disorders ( Justice, 2018 ; Milligan Armstrong et al, 2021 ). The presence of pathogens and other factors such as age, alcohol and tobacco consumption, cerebral hypoxia, metabolic diseases, pollution, sedentary lifestyle, or sleep disorders may cause BBB malfunction ( Noe et al, 2020 ; Hussain et al, 2021 ), and hence lead to the infiltration of neurotoxic proteins such as the β-amyloid peptide ( Wang D. et al, 2021 ).…”