Cholesterol and Neurodegeneration
Thesis Statement: Controlling cholesterol levels within the brain is critical in limiting the development of neurodegenerative diseases
(or Abstract, if the author wants to use the word abstract instead)
Neurodegenerative diseases are rare diseases which cause mental deterioration. Various researches have been conducted since these diseases were first diagnosed and discovered, to find out the true causative agents of these diseases. Neurodgeneration in the humans is also sometimes referred to as dementia of different forms and the diseases included in this category rage from Alzheimer’s to Parkinson’s Disease.
Recently higher cholesterol levels in the brain are being held responsible for causing neurodegeneration and detailed research has been carried by various scientists. This has been observed that lowering the cholesterol level reduces the pathology of Alzheimer’s Disease (AD). However, some other factors also seem to be involved. Scientists have been trying to find out whether improper metabolism of cholesterol in the brain cells is the main cause or are there any other additional factors involved. Prions are infection causing, protein natured particles involved in neurodegenerative diseases. They have been shown to alter the cholesterol levels in the neuron cells, hence cause malfunctioning leading to the onset of neurodegenration.
Cholesterol, its properties and functions in the body cells
Cholesterol is a chemical substance, lipid in nature and required for proper functioning of various structures in the human body. Maximum proportion of cholesterol present in our body is synthesized by the body itself. However, some of it comes from dietary intake as well. Almost all the tissues in the body can manufacture this compound, however, those tissues which have densely packed membranes like liver, spinal cord and reproductive organs produce cholesterol more efficiently and in greater quantities. Its role is indispensable for various cell structures like the cell membranes, for vital chemical reactions taking place in the body like precursor in the synthesis of bile, hormones ( which are steroid in nature), and vitamin D. It is of critical importance that the cells of the major tissues of the body be assured of a continuous supply of cholesterol (Champe & Harvey p.205).
Sterols with 8 to 10 carbon atoms in the side chains at C-17 and hydroxyl group at C-3 are classified as sterols. The structure of cholesterol consists of four fused rings with carbon atoms and a branched hydrocarbon chain. Cholesterol is very hydrophobic. Cholesterol is the major sterol in animal tissue. Much of the plasma cholesterol is in an esterified form which makes the structure even more hydrophobic. Because of this hydrophobicity, cholesterol must be transported either in association with a protein as a component of a lipoprotein particle or solubilized by phospholipids and bile salts in the bile (Champe & Harvey p.206).
Structure of Cholesterol
The importance of cholesterol in the body can be understood by the fact that cholesterol is essential for the growth of mammalian cells and its absence their growth may be halted. Cholesterol is hence found abundantly in almost every part of the body ranging from the cell membranes, to constituent of vitamin D, steroid hormones, and part of myelinated nerve cells. Being a part of the nerve cells also makes it a part of the brain. However, brain is that organ of the body where cholesterol has a different function. In the brain lipoprotein cholesterol of the blood is absent and is not allowed to enter because of the blood brain barrier.
Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450-generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier (Meaney & Björkhem)
In the brain cholesterol carries out numerous important functions like movement across the membranes, signal transduction, formation of myelin, and synaptogenesis.
Cholesterol synthesis in the developing CNS is relatively high, but it declines to a very low level in the adult state. This can be explained by an efficient recycling of brain cholesterol. As a consequence, brain cholesterol has an extremely long half-life; in the adult human brain, the half-life of the bulk of cholesterol has been estimated to be at least 5 years. It was recently pointed out that the long half-life of cholesterol in the brain is remarkable in light of the high metabolic rate of this organ. In humans, the organ-specific metabolic rate of the brain is 9-fold greater than the average metabolic rate of the individual (Meaney & Björkhem).
Nevertheless, some mobility of cholesterol to and from the brain is inevitable and in some circumstances, essential as well. This function is efficiently performed by the brain however; things do not remain the same when abnormalities arise. It is believed by some scientists that excess of cholesterol in the brain is the leading cause of rare neurodegenerative diseases of the brain, while some are of the view that the excess is not the reason but mutation is. The destruction of neurons, which are specified cells for nervous transmission through out the body, is called neurodegeneration
Neurodegenerative diseases and the role of cholesterol
When the basic cells involved in the transmission of nervous impulses, i.e. the neurons, undergo deterioration and degeneration due to any pathological other possible reason, they process is known as neurodegeneration. Loss of memory, decreased IQ and reasoning and emotional as well as personality changes are also observable. All these are the results of “progressive, irreversible, degeneration and atrophy of the cerebral cortex” (Waugh & Grant p.181) which lead to slow mental deterioration. . Neurodegenerative diseases include Alzheimer’s Disease, Huntington’s Disease, Parkinson’s Disease and Amyotrophic lateral sclerosis. Some of these are associated with genetic anomalies while at the same time it is important to note that other factors like “cerebrovascular disease, cerebral trauma, chronic abuse of alcohol and some drugs, vitamin B deficiency, effects of metabolic disorders, e.g. hyperthyroidism, uraemia and liver failure, and last but not the least, infections, e.g. HIV, Creutzfeldt-Jacob disease,” (Waugh & Grant p.181-182) may also cause or aggravate neurodegenerative diseases.
According to research done by various scientists around the world, cholesterol in the brain may also have a role to play in causing mental deterioration diseases.
There is compelling evidence from laboratory research in animal model and cell culture systems, observational epidemiological studies, and small clinical trials that lowering cholesterol may reduce the pathology of Alzheimer’s Disease (AD). In support of link between cholesterol and AD there are in vitro studies demonstrating that cholesterol level modulate the enzymatic processing of the amyloid precursors protein (APP) and consequently AB production. (Beal, et al. p.466)
As mentioned before that metabolic disorder like liver failure may also contribute towards the onset of neurodegenerative diseases. Since liver is a major organ responsible for the metabolism of cholesterol, a failure of liver may result in high concentrations of cholesterol in the blood and its improper metabolism may also lead to its improper homeostasis in the blood as well as the brain. However, these areas are not well researched and a plenty of experimental research is required to establish this type of relationship. Nevertheless, some research in medicine regarding the effects of lowering the cholesterol level in the brain and reduced effects of Alzheimer’s disease do exist.
It is important to understand how cholesterol may be involved in causing these diseases. Research results are not strong enough to support this argument. However, most scientists agree that mutation is responsible in most cases. Sometimes, improper removal or improper movements of cholesterol in the brain are the actual malfunctioning areas consequently leading towards the onset of neurodegeneration. Nevertheless, it is believed by most researchers that cholesterol alone is not the causative agent. Dr. Ingemar Björkhem and Steve Meaney from the Division of Clinical Chemistry, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden state in their research paper, Brain Cholesterol, Long Secret Life Behind a Barrier: “overall, the current data provide tantalizing indications that modulation of intracerebral cholesterol levels may be a possible strategy for protection against Alzheimer disease and possibly also other forms of neurodegeneration.”
Current revelations on this topic justify this concept. An infection causing agent which is protein in nature and known as prion is being held responsible. It is believed to be a virus. It has been well established that the causative agent of Creutzfeldt-Jacob disease is prion. As mentioned before Jacob disease is a neurodegenerative disease and infections may play a part in causing neurodegeneration, scientists have found a new line to follow in finding out the true causative agent of neurodegenerative diseases. Since prion causes the Jacob disease and is also believed to cause the Mad Cow disease in cattle (a neurodegenerative disease in animals), scientists suspect that it also has a role to play in other such diseases as well.
Royal Veterinary College’s (RVC) scientists have been able to reveal the relationship between prions and cholesterol together in causing the neurodegenerative diseases. Prions reportedly increase the amount of free that is unesterified cholesterol in the neurons however; it is also observed that the esterified cholesterol levels are relatively reduced. Hence it can be concluded that prions not only increase the free cholesterol in the cells but also adversely affect its overall metabolism and regulation.
Dr. Clive Bate, Mourad Tayebi and Alun Williams of the department of Pathology and Infectious Diseases, Royal Veterinary College, UK have carried out a research recently and have been able show the effect of prion infection on the level of free cholesterol in the neuron cells and their overall effect on the brain degeneration diseases. Abnormal metabolism of cholesterol in the cells can cause serious type of malfunctioning in the neuron cells. Dr. Clive Bate and colleagues report in their research paper, “Sequestration of free cholesterol in cell membranes by prions correlates with cytoplasmic phospholipase A2 activation”:
We report the novel observation that prion infection altered the membrane composition and significantly increased total cholesterol levels in two neuronal cell lines (ScGT1 and ScN2a cells). There was a significant correlation between the concentration of free cholesterol in ScGT1 cells and the amounts of PrPSc. This increase was entirely a result of increased amounts of free cholesterol, as prion infection reduced the amounts of cholesterol esters in cells. These effects were reproduced in primary cortical neurons (Clive et al).
The proper functioning of the membranes is believed to be subject to the normal cholesterol levels in the brain. This specific research carried out by Dr. Clive and colleagues helps us understand that higher levels of free cholesterol are thought to cause the membranes to function improperly hence leading to the abnormal activation of the enzyme, phospholipase A2. This abnormal activation causes the neurons to undergo deterioration and degeneration. It is also important to note that this free cholesterol levels are believed to be high only due to the infection caused by prions. In the absence of prions when steps are taken to increase the levels of free cholesterol, same deleterious results are not produced. This proves that excess of free cholesterol above the normal value is not possible without the prions causing infection in the neurons. Dr Bate stated: “Our observations raise the possibility that disturbances in membrane cholesterol induced by prions are major triggering events in the neuropathogenesis of prion diseases”.
The relationship between abnormally high levels of free (unesterified) cholesterol in the brain with malfunctioning membranes and the consequent neurodegeneration, which has been suspected for quite a long time, has now been fairly established. In addition, recent research has also revealed a protein based infectious agent, prion, to be the real culprit in not only causing infection but also the cholesterol imbalance in the brain.
Actions which could possibly prevent neurodegeneration include the lowering of free cholesterol in the brain. Since experiments conducted earlier have shown to reduce the pathology of the disease in Alzheimer’s Disease by reducing brain cholesterol levels, further experimentation is required in the same field to establish more profound results and find out the extent to which cholesterol level monitoring in the brain can reduce the pathology. The lowering of cholesterol levels is definitely critical for the reduction of the pathology of this disease.
Bate, Clive. Tayebi, Mourad. Williams, Alun. “Sequestration of free cholesterol in cell
membranes by prions correlates with cytoplasmic phospholipase A2 activation”.
Retrieved from RVC. Royal Veterinary College, University of London. 12 February
2008. Royal Veterinary College. 5 April 2008
Beal, M. Flint et al. Pathogenesis and Therapeutics. Cambridge University Press. 2005.
Champe, Pamela C. and Harvey, Richard A. Lippincott’s Illustrated Reviews: Biochemistry
(2ndEdition). Philadelphia: J.B. Lippincott Company, 1994.
“Cholesterol” (diagram). About.com. 5 April 2008.
Meaney, Steve and Björkhem, Ingemar. “Brain Cholesterol: Long Secret Life Behind a Barrier”
Arteriosclerosis, Thrombosis and Vascular Biology (ATVB). 5 April 2008.
< http://atvb.ahajournals.org/cgi/content/abstract/24/5/806> and
Waugh, Anne and Grant, Allison. Anatomy and Physiology in Health and Illness (Ninth Edition).
Churchill Livingstone. 2002