RESEARCH

Beta-amyloids and Diseases

These “beta-amyloid peptides” are keys to neuron disease

Neurons let us sense and see our world, move our muscles, and think and remember. The APP beta-amyloid precursor protein is produced in neurons throughout the body. Too much cutting of the APP protein releases too many beta-amyloid peptides and is a major cause of neuron degenerative disease in humans. Neurodegenerative disease decreases our ability to sense and see our world, move our muscles, and perhaps most importantly: blocks our ability to think and remember (Alzheimer’ disease).

Beta-amyloids can be produced anywhere in the body. They are generated when the beta-amyloid precursor protein (APP) found in synaptic vesicle membranes in neurons is “cut” by other proteins into separate, smaller sections (peptides). Beta-amyloid peptides derived from APP have important well-defined roles in neuron degenerative disease. Thus, they are considered keys to neuron disease.

Alzheimer’s disease, aging, and diabetes – a chain linked by a common peptide: Beta Amyloids

Aging and diabetes are major factors in Alzheimer’s disease and all three are linked by increased beta-amyloid peptide production. Beta-amyloid peptide solubility and amount of beta-amyloid self-association (oligomer formation) determines the role of beta-amyloid in disease. It is clear that APP beta-amyloid precursor protein gene mutations that increase beta-amyloid production lead to devastating early-onset Alzheimer’s disease.

Recently, a new kind of APP gene mutation was found, which decreases beta-amyloid production and minimizes Alzheimer’s disease risk. Innovative mouse studies also mark the importance of beta-amyloid in Alzheimer disease.

A certain small percentage of Icelandic population essentially does not “get” Alzheimer’s disease” due to genetic mutation in APP (Callaway, 2012). This newly discovered APP gene mutation is unique such that it decreases beta-amyloid in these individuals. Additional researches showed that beta-amyloid solubility, quantity, and composition are key factors that determine its role in the disease process and its clinical manifestation (Murphy & LeVine, 2010). These studies highlight the importance of beta-amyloid levels and different beta-amyloid forms in Alzheimer's disease mechanisms.

Innovative mouse studies also demonstrate the critical role of beta-amyloid in the circulation in Alzheimer’s disease.

The mouse is a mammal that normally cannot “get” Alzheimer’s disease because mice normally produce beta-amyloid peptides whose composition differs from the human beta-amyloid. With this stated fact, a study was conducted (Bu et al., 2017), wherein the bloodstream of a mouse genetically engineered to produce “human-like” disease-causing beta-amyloid peptides was connected to the bloodstream of a normal mouse. As a result, the normal mouse “got” human beta-amyloid Alzheimer brain disease. This means that disease-causing “human” beta-amyloid peptides were able to travel from the genetically modified mouse into the normal mouse brain and produced Alzheimer beta-amyloid pathology including plaques. This further demonstrates the critical role of beta-amyloid in the circulation in Alzheimer’s disease.

Due to aging, the processes that maintain beta-amyloid at low manageable levels becomes dysfunctional, leading to its accumulation and self-association to form oligomers and brain plaques.

Normally, the body keeps beta-amyloid at low manageable levels, but these processes become dysfunctional as the body (and brain) ages (Weller et al., 2008). When beta-amyloid accumulates, it “clumps” easier and forms plaque deposits. Increased beta-amyloid is causally linked with neuron degenerative disease in the brain (Alzheimer’s disease) but also in neurons elsewhere in the body. Beta-amyloid over-production occurs at neuron-muscle junctions in muscle fibers in the major human muscle degenerative disease (Greenberg, 2010): inclusion body myositis (IBM), and in the retina in diabetic retinopathy (Ratnayaka, et al, 2015) (most retina cells are neurons!).

Furthermore, beta-amyloids produced in the brain and throughout body are normally prevented from freely passing into the brain due to the “blood-brain-barrier” separating the brain and its blood system from the rest of the body. However, as we age, this barrier breaks down and allows beta-amyloid peptides to more easily move into (or out of) the brain. (Haridy, 2017). This means beta-amyloids from the circulation can easily enter the brain and add to the brain beta-amyloid load, thereby increasing formation of beta amyloid oligomers and brain plaques which have been classic markers of Alzheimer’s disease (Sadigh-Eteghad S. et al, 2015).

The human aging process is also influenced by metabolic disorders that include impaired blood glucose control and brain trauma. As a result, the formation and disposal of beta-amyloids in the brain is no longer efficient. This increases accumulation of beta-amyloids and plaque formation in the brain (ibid).

There is a growing evidence supporting the link between Type 2 diabetes and Alzheimer's disease, to the extent that some now refer to Alzheimer’s disease as “diabetes of the brain”. Type II diabetics are further at risk of losing both their memory and vision.

Considerable evidence identifies a close link between Type 2 diabetes and Alzheimer's disease (Akter et al, 2011). Similar to the aging process, high blood glucose is closely associated with oxidative stress, a key component of Alzheimer’s disease. Diabetes links with retina degeneration (known as diabetic retinopathy, DR) have been clear for many decades. DR is also a major cause of blindness worldwide. Moreover, studies show that Type II diabetics have a 60% increased risk of developing Alzheimer’s disease and accelerated cognitive decline (Vagelatos & Eslick, 2013).

Globally, over 400 million people have diabetes (WHO, 2016). In the United States, about 30 million are diabetics (CDC, 2017), wherein 90% have Type II aka “adult-onset diabetes”. Type II diabetes has increased at a staggering rate over the past 30 years and is expected to increase again by 50% by 2050 [10]. In relation to the eye, study results demonstrated that the overall prevalence of any DR (in Type I and II diabetes) was 34.6%, with 7% vision-threatening DR (Yau et al, 2012). Otherwise stated, studies from individuals with diabetes showed that they had developed diabetic retinopathy and vision loss.

This information suggests that patients with type II diabetes are at high risks of developing Alzheimer’s disease in addition to the DR they will more likely develop due to diabetes. They have high chances of losing both their memory and their vision. Also, troubling, many individuals are unaware that they are already at the early stages of diabetes.

References

Akter, K., Lanza, E.A., Martin, S.A., Myronyuk, N., Rua, M., and Raffa, R.B. (2011). Diabetes mellitus and Alzheimer’s disease: shared pathology and treatment? British Journal of Clinical Pharmacology. Retrieved from www.ncbi.nlm.nih.gov/.

Bu, X-L, et. al. (2017). Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies. Molecular Psychiatry 00, 1–9. Doi: doi:10.1038/mp.2017.204

Callaway, E. (2012) Gene mutation defends against Alzheimer’s disease. Nature International Weekly Journal of Science. Retrieved 2018 Apr 16 from: www.nature.com/news/

Centers for Disease Control and Prevention. (2017). National Diabetes Statistics Report. Retrieved from: www.diabetes.org

Goodsell, D. (2006). Amyloid-beta Precursor Protein. Retrieved from: http://pdb101.rcsb.org

Greenberg, S. (2010). Theories of the Pathogenesis of Inclusion Body Myositis. Curr Rheumatol Rep. 2(3): 221–228. doi: 1007/s11926-010-0102-5

Haridy, R. 2017. Does Alzheimer’s originate outside the brain? New Atlas. Retrieved from: https://newatlas.com/.

Murphy, M. & LeVine, H. (2010). Alzheimer’s Disease and the β-Amyloid Peptide. J Alzheimers Dis. 19(1): doi: 10.3233/JAD-2010-1221

Nagai, N., et al. (2015). Effect of High Glucose Levels on Amyloid β Production in Retinas of Spontaneous Diabetes Mellitus Otsuka Long-Evans Tokushima Fatty Rats. Biological and Pharmaceutical Bulletin 38(4) 601-610. Retrieved from: doi.org/10.1248/

Projected number of diabetics worldwide in 2045, by region (in millions). Retrieved 2018 May 42 from: www.statista.com/

Ratnayaka, JA., et. al. (2015). Dementia of the eye: the role of amyloid beta in retinal degeneration. Eye (Lond). 29(8): 1013–1026. doi:  1038/eye.2015.100

Sadigh-Eteghad S., Sabermarouf B. , Majdi A. , Talebi M. , Farhoudi M., and Mahmoudi J. (2015). Amyloid-Beta: A Crucial Factor in Alzheimer’s Disease. Medical Principles and Practice 24: 1-10. Retrieved from www.karger.com.

Vagelatos, N. & Eslick, G. (2013). Type 2 Diabetes as a Risk Factor for Alzheimer’s Disease: The Confounders, Interactions, and Neuropathology Associated with This Relationship. Epidemiologic Reviews 3(1), Pages 152–160. Retrieved from: https://doi.org/

Weller, RO., et. al., (2008). Amyloid: Vascular and Parenchymal. Encyclopedia of Neuroscience 355–362. Retrieved from: www.sciencedirect.com/science

World Health Organization. (2016). Global Report on Diabetes. Retrieved from: http://apps.who.int/iris/

Yau, J.W., et. al. (2012). Global Prevalence and Major Risk Factors of Diabetic Retinopathy. Diabetes Care 35(3): 556–564. doi:  2337/dc11-1909

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