The Four Horsemen, a striking metaphor for neurodegenerative brain diseases
With everything that has been going on in 2020, one might think that the horsemen of the apocalypse are here. However, this article is not about the global pandemic, but instead focusses on the silent battle that rages within people suffering from neurodegenerative diseases. Patients diagnosed with chronic conditions such as Parkinson’s, Alzheimer’s, Motor neuron, and Huntington’s disease are unaware that inside their brain, a war against the Four Horsemen has been raging for years. One without the immediate prospect of a cure. In the text Revelation, the appearance of Four Horsemen is a sign of the upcoming apocalypse. One by one the horses and riders appear. The first horseman, a conqueror with a bow and crown, rides a white horse representing three and a half years of peace followed by three and a half years of war. The second horseman carries a great sword and rides a red horse, symbolizing war and bloodshed. He is followed by the third horseman who is holding a balance scale while riding a black horse and embodies famine. The fourth and last horseman rides a pale horse and personifies death.
Neurodegenerative brain diseases are a diverse group of disorders that are characterized by the progressive degeneration of the structure and function of the nervous system. Even though these conditions are very different in origin, age of onset, and symptoms, they follow a similar disease process and are all characterised by the presence of protein clumps within the brain. These clumps cause minimal damage at first, but this apparent peace turns into a death over time, as with the Four horsemen.
Each disorder has its own characteristic protein clumps known as aggregates. Alpha-synuclein aggregates form Lewy bodies and neurites in Parkinson’s disease, whereas both tau tangles and beta-amyloid plaques are present in Alzheimer’s disease. Huntingtin protein aggregates are typically found in Huntington’s disease, an inherited disorder with symptoms that include movement problems and changes in mood. TDP-43 aggregates are present in Motor neuron disease which selectively affects motor neurons, the cells that control voluntary muscles of the body. However, we are slowly learning that a large proportion of patients diagnosed with one disease also carry additional protein aggregates that were thought to be specific to other conditions. In our recent work on Huntington’s disease, a subgroup of cases were found with both tau and huntingtin aggregates when only the latter was expected (1). Another study found that 43% of people with Alzheimer’s disease studied carried two types of protein aggregates, 38% had three protein aggregates, and 12% were found with four types of aggregates (2).
The current hypothesis is that the underlying cause in these brain diseases is multifactorial, involving DNA mutations and/or environmental factors such as exposure to bacteria, viruses, metals, and pesticides. If an external source was the cause, it would explain why in Parkinson’s and Alzheimer’s disease, protein aggregation is first found in areas directly exposed to the outside environment — specifically, the gut and olfactory bulbs. The clinical symptoms are specific to each neurodegenerative condition, but they always progress and worsen over months, years, and in some cases, decades (white horseman). People will appear perfectly healthy, not knowing of the war (red horse) that is being fought inside their brain.
Once the initial aggregate or nucleus is established, it functions as a template to form more aggregates, and the required energy to make bigger aggregates is much lower. The process of aggregate formation, rather than the aggregates themselves, plays a vital role in causing toxicity (black horse). In most instances, the affected cell will be able to break down the aggregates by activating its repair mechanisms (the chaperone and proteasome machinery).
Over time, the sheer amount of aggregates exceeds capacity. At this point, the damage becomes too severe, resulting in the gradual death of brain cells (pale horse). Aging further reduces these protective mechanisms, enabling more aggregates to accumulate and even spread to neighbouring cells, where the process is repeated. Over the course of several years, these aggregates slowly spread into new brain regions, causing the gradual onset of symptoms. It is at this point that people become aware that something is not right. Unfortunately by the time a diagnosis is established, the Four Horsemen caused so much cell death that vital connections are damaged beyond repair. For the time being, there is no cure for these brain diseases. Even though we can treat some of the symptoms, the disease itself gradually worsens over time. Therefor early detection and classification of the brain disease is vital. Intervention that target the underlying disease mechanism is more likely to succeed the earlier we can identify it.
There are several studies currently that aim to detect the disease early, remove the excess of aggregates, and halt the spread to other regions when only the white horse is present. The principle is straightforward: contain the Four Horsemen and limit widespread damage. Some encouraging results are being observed in these studies, with several drugs advancing to the final clinical phases. However, for these therapies, the occurrence of multiple aggregates does complicate things. Therefore we need to change our target and find those cellular mechanisms that are causing the aggregates to form and spread. In doing so, we might find common ground between these neurodegenerative diseases. This way, we can avoid catching a horse that’s bolted but fix the lock to keep the four horses in their stables.
1. Highet, B., Dieriks, B. V., Murray, H. C., Faull, R. L. M. & Curtis, M. A. Huntingtin aggregates in the olfactory bulb in Huntington’s disease. Front. Aging Neurosci. 12, 261 (2020).
2. Karanth, S. et al. Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults. JAMA Neurol. 40536, 1–9 (2020).
