In 1854, German pathologist Rudolf Virchow described his microscopy observations of small round deposits present within the nervous system. The staining techniques used at the time suggested that these deposits were in fact starch, also known as amylum. Thus, Virchow used the term ‘amyloid‘ to describe the deposits. We now know that amyloid is actually formed from proteins, not carbohydrates, but the name amyloid remains.
Amyloid is formed from proteins that aggregate into fibrous deposits to form plaques. These plaques grow around cells and disrupt organ and tissue function, leading to a variety of diseases. Most of the best-known diseases linked to amyloid are neurodegenerative diseases like Alzheimer’s, but amyloid has also been linked other disease of ageing including diabetes, cancer and heart disease, and can affect multiple organs simultaneously. Diseases caused by amyloid formation can be referred to collectively as amyloidosis.
Amyloid is formed from proteins – large, complex molecules that are built from hundreds or thousands of smaller units called amino acids. These amino acids are joined together to form a protein chain, which then folds upon itself to produce a three-dimensional structure. The arrangement of amino acids within the protein determines where and how the protein will fold, and the final shape of the protein determines what its function within the body will be. The video below depicts a protein folding as it is being built from its constituent amino acids by a ribosome.
Normal, healthy proteins will not aggregate to form amyloid. Unfortunately, with millions upon millions of copies of a given protein being made during our lifetimes, the folding process doesn’t always occur correctly. When a protein misfolds and assumes the wrong shape, it may not properly fulfil its function, and may even become harmful. To minimise this occurrence, our cells have evolved a complex quality control system to correct or remove misfolded proteins. However, these systems become less effective as we age, allowing more and more errors to slip through the net. Once-healthy proteins can also misfold or partially unfold at some time after they have been made and released from a cell.
37 human amyloid proteins have so far been confirmed to be capable of causing disease. Well known examples include amyloid β in Alzheimer’s disease, α-synuclein in Parkinson’s disease, and huntingtin in Huntington’s disease.
In addition to these neurodegenerative diseases, amyloidosis can also cause or contribute to other diseases. In diabetes, for example, beta cells in the pancreas must ramp up their production of the hormone insulin in an attempt to maintain control of blood sugar. This puts strain on the beta cells’ ‘protein factories’ and can cause proinsulin (a precursor to insulin) to misfold. The resulting amyloid damages the beta cells and contributes further to the progression of diabetes. Another example is transthyretin cardiomyopathy, in which an amyloid protein called transthyretin builds up in the walls of the heart, leading to stiffening and heart failure.
Unfortunately, we still don’t have a definite answer as to why amyloid causes disease. In some cases, amyloid may physically disrupt the tissue and thus cause damage to the organ. However, the link between amyloid and disease is not always as straightforward as one might assume. For example, some individuals with amyloid can live to an advanced age without developing neurodegenerative disease, despite showing levels of amyloid plaque similar to those dying with dementia.
One possible explanation for this is that it is not always the amyloid plaque itself that causes the majority of the damage, but rather the intermediate aggregates involved in the plaque’s formation. Thus, an individual could slowly accumulate a large amount of amyloid plaque over time, all the while maintaining relatively low levels of intermediate structures and avoiding significant tissue damage.
Another process that is likely to play a key role in the damage caused by amyloid is inflammation. The inflammatory response is the immune system’s way of rapidly dealing with a foreign pathogen, and can be triggered by any source of damage such as that caused by amyloid. However, when the inflammatory cells are unable to remove the cause of the damage, inflammation continues indefinitely. Chronic inflammation is seriously disruptive for the tissue in question, and also results in a vicious cycle, since inflammation can accelerate amyloid formation.
Some level of amyloid formation may unavoidable, but our evidence suggests that amyloid– related diseases are not necessarily an inevitable part of ageing. The extent to which environmental factors impact amyloid formation and disease risk compared with genetic factors varies from one disease to another. However, generally, amyloid pathology can be improved through all of the lifestyle practices that we associate with good health, particularly regular exercise and a healthy diet low in sugar, alcohol and processed meats, while avoiding smoking.
There are other more minor lifestyle adjustments that may further reduce risk of amyloid-associated diseases. Antioxidants capable of reducing levels of chronic inflammation, such as flavonoids found in nearly all fruits and vegetables, may reduce the risk of some amyloid-associated diseases. It may be possible to reduce amyloid formation by consuming foods with above average flavonoid content, although the overall benefits of a healthier diet and more exercise are likely to be more consequential.
There is also some evidence that caffeine may reduce amyloid deposition in the brain and thus protect against Alzheimer’s disease and some other forms of amyloidosis. Coffee and certain teas are of interest as they contain both caffeine and the aforementioned flavonoids. For example, some studies suggest that lifetime coffee consumption lowers amyloid deposition and reduces the risk of Alzheimer’s, while a recent small study suggested that green tea might slow transthyretin amyloidosis in the heart.
Perhaps the most extreme measure one could take with the aim of reducing amyloidosis is to practice dietary restriction such as calorie restriction or fasting. Experiments in mice suggest that calorie restriction can reduce multiple types of amyloidosis, and there is good reason to believe that this may also work in humans, since calorie restriction has been associated with reduced risk of age-related diseases including Alzheimer’s.
“Amyloid” — Historical Aspects: https://www.intechopen.com/books/amyloidosis/-amyloid-historical-aspects
The Role of Inflammation in Amyloid Diseases: https://www.intechopen.com/books/amyloid-diseases/the-role-of-inflammation-in-amyloid-diseases
Protein Misfolding and Degenerative Diseases: https://www.nature.com/scitable/topicpage/protein-misfolding-and-degenerative-diseases-14434929/
Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164555/
Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes: https://doi.org/10.1016/j.mam.2015.01.001
Caloric restriction reduces the systemic progression of mouse AApoAII amyloidosis: https://dx.doi.org/10.1371%2Fjournal.pone.0172402
Caloric restriction attenuates amyloid deposition in middle-aged APP/ PS1 mice: https://dx.doi.org/10.1016%2Fj.neulet.2009.08.038
Green tea halts progression of cardiac transthyretin amyloidosis: an observational report: https://doi.org/10.1007/s00392-012-0463-z
Caloric restriction: beneficial effects on brain aging and Alzheimer’s disease: https://doi.org/10.1007/s00335-016-9647-6
Oligomeric Intermediates in Amyloid Formation: Structure Determination and Mechanisms of Toxicity: https://doi.org/10.1016/j.jmb.2012.01.006