By Chris Masterjohn
One of the many important roles cholesterol plays in the body is in our nervous system, enabling learning and memory to take place. In fact, one of the reasons that sleep is beneficial to our learning and memory is because it enables our brain to make more cholesterol!
While the war on cholesterol is waged full-speed ahead, and many web sites are now touting low-fat, low-cholesterol diets as "brain-healthy" due to unfortunate misinterpretations about the role of a cholesterol byproduct in Alzheimer's disease, science is continually showing that cholesterol is one of the most important parts of our brains.
Sleep, Memory, Learning... and Cholesterol
Evidence to date strongly supports the concept that sleep plays an important role in increasing performance of newly learned activities, consolidating memories, and increasing brain plasticity-- which is the ability to form new, as well as break, connections between neurons called synapses.
These benefits of sleep are not simply the absence of stress from sleep-deprivation, but an independent, critical role, in the actual process of learning and memory-formation.1
Exciting research was published in the pages of Neuron last year (2004),2 identified about 100 genes that increase their activity during sleep. They found about as many that increased their activity during wake, and others whose activity varied with circadian rhythm, independent of sleep or wakefulness.
While there are many important cellular and molecular events that happen during sleep, and we are only cracking the surface in our understanding of them, one of the things this study showed is that cholesterol synthesis increases during sleep-- which, given the research described below, undoubtedly is part of the reason sleep is beneficial to mental functioning.
Cholesterol is abundant in the tissue of the brain and nervous system. Myelin, which covers nerve axons to help conduct the electrical impulses that make movement, sensation, thinking, learning, and remembering possible, is over one fifth cholesterol by weight.3
Even though the brain only makes up 2% of the body's weight, it contains 25% of its cholesterol.4
One of the groups of genes that the above study found to be upregulated during sleep were genes important for the synthesis and maintenance of myelin, including myelin structural proteins and genes relating to the synthesis and transport of cholesterol.
But the benefits of cholesterol extend beyond both sleep and myelin. In fact, in 2001, cholesterol was found to be the most important factor in the formation of synapses, the basis of our learning and memory.
Memories and Learning are Directly Dependent on Cholesterol
In the late 1990s and early 2000s, research was pointing to an unknown compound made by glial cells that was responsible for the ability of neurons to form synapses, or connections between each other.
Thoughts, memories, learning, and all mental function is dependent on the formation of synapses, so the ability to form them will directly impact mental functioning and health.
In the absence of this-- as yet unknown-- "glial factor," neurons formed few synapses, and the synapses they formed were inefficient and poorly functioning. In the presence of glial cells, which secrete the unknown factor, neurons formed many, highly efficient synapses.
So what is this "glial factor"?
Research in 2001, by Mauch, et al., published in volume 294 of Science magazine, determined that the unknown glial factor is cholesterol, which is released by the glial cells in a carrier called "apolipoprotein E."5
Initially, the researchers thought that the apolipoprotein E (apoE) may have been the glial factor itself. But it turned out that when neurons were treated with apoE, the beneficial effects on synapse formation were not observed.
The researchers then reasoned that, since apoE fit the bill in some ways, but did not have the desired effect, some of the lipids it carried may have been the elusive glial factor.
As it turned out, treating the neurons with a 10 mcg/mL solution of cholesterol increased synapse formation by 12 times! Other lipids, carried by apoE, such as phosphatidylcholine and sphingomyelin, did not have a significant effect, and were even toxic to the neurons at very high doses.
On the other hand, when low-cholesterol glial secretions were produced by using the cholesterol-lowering drug, mevastatin, the effect of the glial secretion on synapse formation was strongly diminished. When cholesterol was added back to the low-cholesterol secretion, the positive effect on synapse formation was fully restored.
The authors identified cholesterol as a limiting factor of synpase formation. In other words, the need for cholesterol in the brain is large enough relative to the supply of cholesterol that the availability of cholesterol can directly limit the ability to form synapses.
Neurites Lose Their Way Without Cholesterol
"Neurites" refer to the extensions from the cell of a neuron that connect with other neurons or muscles. The type of neurite that sends impulses away from the cell is an axon, and the type of neurite that receives impulses is a dendrite.
Connections between neurons, called synapses, are contantly being formed and broken in our brains, where dendrites and axons meet.
But they can't just grow randomly. Neurites grow in response to a stimulus given by a signaling protein in the membranes of neurons.
These signaling proteins rely on lipid rafts, which are beds of cholesterol and phospholipids made from long-chain saturated fatty acids that secure some proteins.
A 2004 study found that disrupting lipid rafts by extracting some of the cholesterol from the membrane of a neuron completely destroyed the ability of neurons to find the signaling proteins attracting them!6
Statins Could Kill Your Memory -- Eggs Could Cure It
We now know that the formation of synapses, or connections between neurons, is directly dependent on the availability of cholesterol.
The formation of these synapses are what give us the ability to remember and learn. The benefits of sleep for memory formation and learning are in part a result of increased cholesterol synthesis during sleep.
The implications are important and powerful. In our society's quest to lower cholesterol at all costs and without second thought, could some of the methods we use, such as taking cholesterol-lowering drugs, or eating low-fat, low-cholesterol diets, be limiting the availability of cholesterol to our nervous system?
The authors of the 2001 Science study described above concluded that the "results imply that genetic or age-related defects in the synthesis, transport, or uptake of cholesterol in the CNS may directly impair the development and plasticity of the synaptic circuitry."
But the authors left out one thing: in addition to genetic or age-related defects, there is currently a boombing industry founded upon the deliberate inhibition of the synthesis of cholesterol using pharmaceutical drugs. Some statins cross the blood-brain barrier (BBB); others may affect cholesterol levels in the brain without necessarily crossing the BBB; still, without crossing the BBB, the peripheral nervous system could likewise be damaged.
In fact, amnesia and cognitive dysfunction are reported as side-effects in some statin users. Dr. Duane Graveline, MD, former NASA scientist and astronaut, describes his bout of statin-induced memory loss, in which his wife caught him wandering aimlessly in his yard while he failed to recognize her.
In an article on the side-effects of cholesterol-lowering drugs, the Geriatric Times cites two randomized trials, several case reports, and one large case series pointing to memory loss as a result of statin drugs.
Conversely, dietary cholesterol can help reverse the effects of declining memory with age.
Mary Enig, PhD, cites a study in her book, Know Your Fats, that found that the cholesterol in eggs can help improve memory in the elderly.5
One of the basic parts of ourselves that defines us as humans is our mind. We imagine, think, study, learn, remember, come up with new ideas, remember old faces, and form friendships and familial relationships that are based, in large part, on our memories of those people.
Cholesterol is a central building block of the connections within our brain that hold these memories and learning processes together. Remember that... thanks to cholesterol, you can!
1. Walker, et al., "Sleep-Dependent Learning and Memory Consolidation" (Review), Neuron, Vol. 44, 121-133, September 30, 2004.
2. Cirelli, et al., "Extensive and Divergent Effects of Sleep and Wakefulness on Brain Gene Expression," Nueron, Vol. 41, 35-43, January 8, 2004.
3. Alberts, et al., Molecular Biology of the Cell: Fourth Edition, New York: Garland Science, 2002, p589F.
4. Dietschy JM, Turley SD, "Cholesterol metabolism in the brain," Curr Opin Lipidol, 2001, 12: 105-112.
5. Mauch et al., "CNS Synaptogenesis Promoted by Glia-Derived Cholesterol," Science, Vol. 294, 1354-1357.
6. Guirland, et al., "Lipid Rafts Mediate Chemotropic Guidance of Nerve Growth Cones," Neuron, Vol. 42, 51-62, April 8, 2004.
7. Enig, Mary G., PhD, Know Your Fats: The Complete Primer for Understanding the Nutrition of Fats, Oils, and Cholesterol, Silver Spring: Bethseda Press, 2000, p. 57.