The Myth about Cholesterol and its Causes
“If you look at, you talk about observation, you talk about the look at myeloid, take the Framingham study that's trying to show that cholesterol causes heart disease. That's gone on for 30 years. They haven't shown up for 30 years of research, they haven't shown that cholesterol is correlated to heart disease. And it showed that people with very high cholesterol have the lowest risk of dementia and all the other psychiatric illnesses. Now, putting that back into science, 70 to 80 percent of your brain is cholesterol. Your myelin sheath is 100 percent cholesterol.All your hormones are cholesterol. So what are we doing?
They've
only shown that decreasing your cholesterol with the statin will give you a 1.6
percent benefit. What's 1.6 percent benefit? You can say 1.6 percent, Philip,
but tell a statistician that and you tell you it's not significant. It can be
an error. Remember, if you're looking for something, you're not going to find
what you weren't looking for.
Now, when
you look at that same Framingham study, it didn't show a link between
cholesterol and heart disease for the last 40 years.”
Despite publications highlighting the importance of cholesterol for the brain—both to prevent demyelination and to support the synthesis of myelin-forming oligodendrocytes, a critical process for the proper formation and maintenance of myelin (the insulating sheath that wraps around axons in the central nervous system, or CNS)—statins continue to be prescribed.
Cholesterol synthesis in myelin-forming oligodendrocytes is a critical process for the proper formation and maintenance of myelin, the insulating sheath that wraps around axons in the central nervous system (CNS). Cholesterol is a major lipid component of myelin, contributing significantly to its structural integrity and function. Oligodendrocytes synthesize cholesterol de novo, as the blood-brain barrier prevents the direct uptake of circulating cholesterol into the CNS.
Here’s an overview of the process:
1. Cholesterol Synthesis Pathway in Oligodendrocytes
Oligodendrocytes utilize the mevalonate pathway, a multi-step process that synthesizes cholesterol from acetyl-CoA:
a) Formation of Mevalonate (Committed Step)
The process begins in the cytosol with acetyl-CoA, which is derived from glucose metabolism or fatty acid oxidation.
HMG-CoA synthase converts acetyl-CoA into HMG-CoA (3-hydroxy-3-methylglutaryl-CoA).
HMG-CoA reductase (the rate-limiting enzyme in cholesterol biosynthesis) reduces HMG-CoA to mevalonate, a critical intermediate. This step is tightly regulated by feedback inhibition from cholesterol and its derivatives.
b) Formation of Isoprenoids
Mevalonate is converted into isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) through several phosphorylation steps.
IPP and DMAPP are then used to build longer isoprenoid chains, forming geranyl pyrophosphate (GPP) and farnesyl pyrophosphate (FPP).
c) Synthesis of Squalene
Two molecules of FPP are condensed by the enzyme squalene synthase to form squalene, the first committed precursor to cholesterol.
d) Formation of Lanosterol
Squalene undergoes oxidation by squalene epoxidase, followed by cyclization via lanosterol synthase, to produce lanosterol.
e) Conversion of Lanosterol to Cholesterol
Lanosterol is then converted to cholesterol through a series of 19 enzymatic reactions, many of which occur in the smooth endoplasmic reticulum (ER). This process includes the removal of methyl groups, reduction of double bonds, and isomerization.
2. Regulation of Cholesterol Synthesis in Oligodendrocytes
Since myelination requires large amounts of cholesterol, oligodendrocytes tightly regulate its synthesis:
SREBP-2 (Sterol Regulatory Element-Binding Protein-2): A transcription factor that regulates the expression of genes involved in cholesterol synthesis (e.g., HMG-CoA reductase, squalene synthase). When intracellular cholesterol levels are low, SREBP-2 is activated and upregulates cholesterol biosynthesis.
Feedback Inhibition: Excess cholesterol inhibits HMG-CoA reductase activity and prevents overproduction.
Oxysterols: Cholesterol derivatives, such as 24S-hydroxycholesterol, also serve as feedback inhibitors for cholesterol synthesis.
3. Cholesterol Transport and Myelin Assembly
Once synthesized, cholesterol is transported within the oligodendrocyte and incorporated into myelin:
Lipid Rafts: Cholesterol is enriched in lipid rafts, which are specialized membrane microdomains that provide structural support for myelin proteins such as myelin basic protein (MBP) and proteolipid protein (PLP).
Myelin Synthesis: Cholesterol, along with other lipids (e.g., galactosylceramides, sphingomyelin), forms the lipid bilayer of myelin. Cholesterol stabilizes the compact arrangement of lipids and proteins within the myelin sheath.
4. Importance of Cholesterol Synthesis for Myelination
Oligodendrocytes are the primary source of cholesterol for myelin in the CNS. In contrast to other cells that might rely on extracellular cholesterol, oligodendrocytes rely on de novo synthesis because peripheral cholesterol cannot cross the blood-brain barrier.
Cholesterol synthesis peaks during active myelination (e.g., during brain development and remyelination following injury).
Disruptions in cholesterol synthesis can impair myelination, as observed in demyelinating diseases like multiple sclerosis (MS) or in genetic disorders affecting enzymes in the cholesterol biosynthetic pathway (e.g., Smith-Lemli-Opitz syndrome).
5. Therapeutic and Experimental Implications
Targeting HMG-CoA Reductase: While statins inhibit HMG-CoA reductase to lower cholesterol in peripheral tissues, their impact on CNS cholesterol and myelination must be carefully considered.
Promoting Remyelination: Enhancing cholesterol synthesis in oligodendrocytes is a potential therapeutic strategy to promote remyelination in demyelinating disorders.
In summary, oligodendrocytes synthesize cholesterol de novo using the mevalonate pathway, which provides the building blocks for myelin assembly and maintenance. This synthesis is essential for proper CNS function and is tightly regulated to meet the high cholesterol demands of myelination.
The pathological consequences of demyelination.
Demyelination, the loss or damage of the myelin sheath surrounding axons, leads to profound pathological consequences due to the critical role myelin plays in the central nervous system (CNS) and peripheral nervous system (PNS). Myelin is essential for rapid signal conduction, axonal protection, and neural communication. When demyelination occurs, it disrupts these processes, leading to neurological dysfunction. Below is an explanation of the pathological consequences and mechanisms underlying demyelination:
1. Pathological Consequences of Demyelination
a) Slowed or Blocked Nerve Signal Conduction
Myelin acts as an insulator that allows for saltatory conduction, where electrical signals jump from one node of Ranvier to the next, significantly increasing signal speed.
Demyelination exposes axons, causing a loss of saltatory conduction. As a result:
Signal conduction becomes slower and less efficient.
In severe cases, conduction can be completely blocked, leading to paralysis, sensory loss, or cognitive impairments depending on the affected pathways.
b) Axonal Damage and Neurodegeneration
Myelin not only facilitates conduction but also provides metabolic and trophic support to axons.
Loss of myelin increases the vulnerability of axons to:
Oxidative stress: Demyelination can expose axons to reactive oxygen species (ROS), leading to structural damage.
Excitotoxicity: Dysregulated glutamate signaling in demyelinated areas can overactivate axonal glutamate receptors, leading to calcium influx and axonal degeneration.
Physical Stress: Without myelin, axons are less mechanically stable and prone to breakage.
Over time, this leads to irreversible axonal loss, contributing to long-term neurological disability.
c) Inflammation and Immune-Mediated Damage
Demyelination often triggers or is caused by inflammatory processes.
In conditions like multiple sclerosis (MS), the immune system attacks myelin, leading to:
Chronic inflammation.
Recruitment of immune cells (e.g., microglia, macrophages, T cells) that further damage myelin and axons.
The resulting inflammatory environment exacerbates neuronal damage and delays remyelination.
d) Cognitive and Neurological Deficits
The specific consequences of demyelination depend on the location of the affected axons:
CNS Demyelination (e.g., in MS or leukodystrophies):
Sensory deficits (e.g., vision loss in optic neuritis).
Motor impairments (e.g., weakness, spasticity).
Cognitive dysfunction (e.g., memory loss, slowed information processing).
Fatigue and coordination problems (e.g., ataxia).
PNS Demyelination (e.g., in Guillain-Barré syndrome):
Peripheral neuropathy (e.g., numbness, tingling).
Muscle weakness or paralysis.
Autonomic dysfunction (e.g., heart rate or blood pressure instability).
e) Impairment of Remyelination
In healthy tissue, oligodendrocyte progenitor cells (OPCs) can differentiate into mature oligodendrocytes and remyelinate damaged axons.
In chronic demyelinating diseases, remyelination often fails due to:
Exhaustion of OPC populations.
A hostile inflammatory microenvironment.
Axonal loss (remyelination cannot occur if the axon itself is destroyed).
This failure to remyelinate exacerbates the progression of neurodegenerative disorders.
2. Demyelination in Specific Diseases
Demyelination occurs in a variety of CNS and PNS pathologies, each with unique causes and consequences:
a) Multiple Sclerosis (MS)
Cause: Autoimmune attack on CNS myelin, likely triggered by genetic and environmental factors.
Consequences:
MS plaques or lesions in the brain and spinal cord, resulting in focal demyelination.
Neurological symptoms such as vision loss, motor weakness, sensory changes, and cognitive decline.
Long-term axonal damage and neurodegeneration, leading to progressive disability.
b) Leukodystrophies
Cause: Genetic disorders affecting myelin production or maintenance (e.g., mutations in enzymes required for lipid metabolism).
Consequences:
Developmental delays, motor dysfunction, and cognitive impairment.
Example: Krabbe disease involves toxic accumulation of galactosylsphingosine, damaging oligodendrocytes.
c) Guillain-Barré Syndrome (GBS)
Cause: Autoimmune attack on PNS myelin, often triggered by infections (e.g., Campylobacter jejuni).
Consequences:
Rapid-onset muscle weakness or paralysis.
Respiratory failure in severe cases.
Most patients recover, but some experience chronic neuropathy.
d) Progressive Multifocal Leukoencephalopathy (PML)
Cause: Infection of oligodendrocytes by the JC virus, often in immunocompromised individuals (e.g., HIV/AIDS, organ transplant recipients).
Consequences:
Widespread CNS demyelination.
Severe cognitive and motor impairments, often fatal.
e) Central Pontine Myelinolysis (CPM)
Cause: Rapid correction of hyponatremia (low sodium levels).
Consequences:
Demyelination in the central pons.
Symptoms include quadriplegia, dysphagia, and locked-in syndrome.
3. Mechanisms of Disease Progression
Demyelination induces a cascade of pathological events that worsen neurological outcomes:
a) Energy Failure
Loss of myelin increases the energy demands on axons, as they need more ATP to maintain ion gradients and propagate signals. This energy failure can lead to axonal degeneration.
b) Altered Ion Homeostasis
Demyelinated axons experience abnormal sodium and calcium influx due to exposed ion channels, leading to cellular toxicity and eventual axonal death.
c) Glial Scarring (Astrogliosis)
In response to chronic demyelination, astrocytes form a glial scar, which creates a physical and biochemical barrier that inhibits remyelination and axonal repair.
d) Chronic Neuroinflammation
Persistent inflammation leads to ongoing damage to both myelin and axons, creating a vicious cycle of degeneration and failed repair.
4. Clinical Manifestations of Demyelination
Demyelination can manifest in a variety of ways depending on the region affected:
Cognitive impairment (e.g., memory loss, confusion): Seen in MS or PML.
Motor deficits (e.g., weakness, spasticity): Common in MS, leukodystrophies, and GBS.
Sensory loss (e.g., numbness, tingling): Often seen in GBS and MS.
Autonomic dysfunction (e.g., abnormal heart rate, blood pressure): Common in PNS demyelinating conditions like GBS.
Visual problems (e.g., optic neuritis): A hallmark of MS.
5. Therapeutic Implications
Reducing Inflammation: Anti-inflammatory treatments (e.g., corticosteroids, immune-modulating drugs) can slow disease progression in conditions like MS.
Promoting Remyelination:
Strategies include stimulating oligodendrocyte precursor cells or targeting pathways that enhance their differentiation.
Examples: Experimental therapies such as clemastine (an antihistamine) or other remyelinating agents.
Neuroprotection: Preventing axonal damage through antioxidants, calcium channel blockers, or glutamate antagonists.
Summary
Demyelination leads to disrupted neural signaling, axonal damage, neurodegeneration, and functional impairments across motor, sensory, and cognitive domains. Understanding the underlying mechanisms of demyelination and its consequences is critical for developing effective therapies to slow disease progression, enhance remyelination, and improve patient outcomes.
Reference:
High cholesterol level is essential for myelin membrane growth https://pubmed.ncbi.nlm.nih.gov/15793579/
The Myelin Sheath: https://www.ncbi.nlm.nih.gov/books/NBK27954/
Cholesterol Controversy:
Framingham
Heart Study (FHS)
“It stated that- “cholesterol does not cause heart disease in the elderly and
trying to reduce it with drugs such as statins is a waste of time- an
international group of experts has claimed”. A review of research involving
nearly 70,000 people found that there was no link between what has
traditionally been considered “bad“ cholesterol and the premature deaths of
over 60-year-old individuals from CVD. In the BMJ open journal, the new study
found that 92% of people with a high cholesterol level lived longer.” https://journals.lww.com/jcpc/fulltext/2018/07010/cholesterol_controversy.1.aspx
Alternative LDL Cholesterol–Lowering Strategy vs High-Intensity Statins in Atherosclerotic Cardiovascular DiseaseA Systematic Review and Individual Patient Data Meta-Analysis
https://jamanetwork.com/journals/jamacardiology/fullarticle/2826516?guestAccessKey=74277a70-4150-42e8-a7a7-d09d4ef5aed9&utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jamacardiology&utm_content=olf&utm_term=112024&adv=
© 2000-2025
Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year
copy right.
Library of Congress Card Number: LCN 00-192742
ISBN:
0-9703195-0-9
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