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Stress and neurodegeneration- different moods

Stress and neurodegeneration

Cortisol is a glucocorticoid steroid hormone produced by the zona fasciculata segment of the adrenal gland, following stimulation by the release of adrenocorticotropic hormones from the pituitary gland. Chronic stress is associated with excessive cortisol production and the development of neurodegenerative diseases. 

Once cortisol is produced and released into circulation, it crosses the blood-brain barrier to bind to and activate nuclear glucocorticoid receptors (GR) in the hippocampus. Upon cortisol binding, the GR undergoes conformational changes, causing it to dissociate from its chaperone complex and consequently allowing for the transcription of target genes. 

One such pathway that is activated as a result of GR binding is the brain-derived neurotrophic factor (BDNF) and the cAMP response element-binding protein (CREB) pathway, which is important for long-term memory formation and consolidation. 

However, memory formation can be impaired following abnormal BDNF/ CREB pathway activation due to elevated cortisol levels. Moreover, high cortisol levels have been found to cause increased amyloid-beta (AB) deposition, which is evident in Alzheimer's disease patients. Therefore, increased blood cortisol levels result in increased activation of GR, causing impaired gene expression and affecting cellular functions. When GR are exposed to cortisol over a long period of time, such pathways become further impaired, resulting in the characteristic neurodegenerative disease pathology in affected individuals. 

A study conducted by Kline et. al assessed the relationship between high cortisol levels and neurodegenerative disease pathology in mice. In this study, it was noted that chronic stress reduced the diversity of the gut microbiome in mice, and such alterations resulted in increased gut permeability, promoting the movement of pathogens across the epithelial lining, and increasing AB deposition in affected mice. 

However, AB deposition can be reduced if cortisol levels are controlled. For example, xanamem, a drug currently in clinical trials, reduces cortisol levels by inhibiting the 11B-hydroxysteroid-1 ezyme, known to play a role in the activation of cortisol via the hypothalamus-pituitary-adrenal axis. Therefore, xanamem or similar compounds, if suitable following clinical testing, could be a means of decreasing AB deposition, thereby targeting one component of neurodegnerative disease pathology. If the putative hypotheses of Alzheimer's disease aetiology are correct, this would potentially ameliorate patient symptoms and offer a degree of improved quality of life for affected individuals.


By Maria Zareef Kahloon 

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