Alzheimer’s disease (AD) can be brought on by many factors including one’s genome, lifestyle, and stress levels. How stress affects one’s risk for AD is poorly understood, yet a research team (Park et al., 2015) recently determined that the physiological and mechanistic steps in the stress cascade might enhance the formation of amyloid plaques.
Using mouse and human neuronal cells, the researchers were able to demonstrate increases in amyloid beta (Aβ, the main peptide component of amyloid plaques) production after treatment with corticotrophin releasing factor (CRF). This is accomplished via the co-localization of the bound CRF receptor 1 (CRFR1) and γ-secretase, the enzyme that cleaves amyloid precursor protein (APP) into Aβ peptides. Thus, when CRF binds CRFR1, γ-secretase is localized to the area and begins producing Aβ peptides, ultimately producing harmful amyloid plaques (see Figure 6 below, adapted from Park et al., 2015).
This mechanism bears bad news for your risk for Alzheimer’s if you are a chronically stressed individual. When stressed, your hypothalamic-pituitary axis is constantly being activated. Your hypothalamus releases CRF into the hypopheseal portal, eventually triggering the anterior pituitary to secrete ACTH, leading to cortisol release by the adrenal cortex. The elevated levels of CRF in neuronal cells, however, will lead to this activation of γ-secretase, which may then cause an increase in Aβ peptide production in the brain. A greater accumulation of Aβ peptides increases your chance of developing Alzheimer’s disease. Long story short, learn to handle chronic stress if you wish to lower your chances of developing Alzheimer’s.
Figure 6. Mechanism of γ-secretase activation in both (A) CRFR1-dependent and (B) CRFR1-independent pathways (Park et al., 2015).
Reference
Park, H. J., Ran, Y., Jung, J. I., Holmes, O., Price, A. R., Smithson, L., ... & Felsenstein, K. M.
(2015). The stress response neuropeptide CRF increases amyloid‐β production by regulating γ‐ secretase activity. The EMBO Journal, 34, 1674-1686.
http://emboj.embopress.org/content/embojnl/34/12/1674.full.pdf
What interests me is that gamma secretase is an intermembrane protein. So, when the function is connected to CRF, does CRF have intracellular effects that either drive the synthesis or activation of the gamma secretase protein? If so, what is the function of gamma secretase without the influence of CRF? Since AD is deemed a "disorder," that indicates that there is something abnormal happening. Obviously the increase in amyloid beta has a phenotypic effect, but since gamma secretase has APP proteolytic activity, does it normally cleave APP into amyloid beta?
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ReplyDeleteAlzheimer’s disease effects so many and can be detrimental to families, so I am glad you brought some attention to this important topic. You proposed increased chronic stress as a contributor to Alzheimer’s. I recently posted a blog on the power meditation has to physically change the brain and reduce stress. Meditation may be more important than I thought as a possible preventative care for many health problems- including Alzheimer’s. I found an article supporting this below on PubMed:
ReplyDeletehttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005947/
I have found research that supports that meditation is shown to reduce cortisol levels. Even though this does not directly reduce CRF levels in neuronal cells, it might be interesting to find out if this still reduces risk of Alzheimer’s, seeing as how is the increased CRF that might eventually lead to increased AB peptides and a higher chance of Alzheimer’s disease.
Vandana B, Vaidyanathan K, Saraswathy L, Sundaram K, Kumar H. Impact of Integrated Amrita Meditation Technique on Adrenaline and Cortisol Levels in Healthy Volunteers. Evidence-Based Complementary & Alternative Medicine (Ecam) [serial online]. January 2011;8(1):1-6. Available from: Academic Search Premier, Ipswich, MA. Accessed October 12, 2015.