Thursday, December 17, 2009

8. Cholesterol's Role in the Brain

The brain comprises only 2% of the body's total weight, yet it contains nearly 25% of the total cholesterol in the body. It has been determined that the limiting factor allowing the growth of synapses is the availability of cholesterol, supplied by the astrocytes. Cholesterol plays an incredibly important role in the synapse, by shaping the two cell membranes into a snug fit so that the signal can easily jump across the synapse [49]. So inadequate cholesterol in the synapse will weaken the signal at the outset, and inadequate fat coating the myelin sheath will further weaken it and slow it down during transport. A neuron that can't send its messages is a useless neuron, and it only makes sense to prune it away and scavenge its contents.

The neurons that are damaged in Alzheimer's are located in specific regions of the brain associated with memory and high level planning. These neurons need to transmit signals long distances between the frontal and prefrontal cortex and the hippocampus, housed in the midbrain. The transport of these signals depends on a strong and tight connection in the synapse, where the signal is transferred from one neuron to another, and a secure transmission across the long nerve fiber, a part of the white matter. The myelin sheath which coats the nerve fiber consists mainly of fatty acids, along with a substantial concentration of cholesterol. If it is not well insulated, the signal transmission rate will slow down and the signal strength will be severely reduced. Cholesterol is crucial for the myelin as well as for the synapse, as demonstrated dramatically through experiments conducted on genetically defective mice by Gesine Saher et al. [45]. These mutant mice lacked the ability to synthesize cholesterol in myelin-forming oligodendrocytes. They had severly disturbed myelin in their brains, and exhibited ataxia (uncoordinated muscle movements) and tremor. In the abstract, the authors wrote unequivocally, "This shows that cholesterol is an indispensable component of myelin membranes."

In a post-mortem study comparing Alzheimer's patients with a control group without Alzheimer's, it was found that the Alzheimer's patients had significantly reduced amounts of cholesterol, phospholipids (e.g, B-HDL), and free fatty acids in the cerebrospinal fluid than did the controls [38]. This was true irrespective of whether the Alzheimer's patients were typed as apoE-4. In other words, reductions in these critical nutrients in the spinal fluid are associated with Alzheimer's regardless of whether the reduction is due to defective apoE. The reductions in fatty acids were alarming: 4.5 micromol/L in the Alzheimer's patients, compared with 28.0 micromol/L in the control group. This is a reduction by more than a factor of 6 in the amount of fatty acid available to repair the myelin sheath!

People with the apoE-4 allele tend to have high serum cholesterol. The question of whether this high cholesterol level might be an attempt on the part of the body to adjust for a poor rate of cholesterol uptake in the brain was addressed by a team of researchers in 1998 [39]. They studied 444 men between 70 and 89 years old at the time, for whom there existed extensive records of cholesterol levels dating back to several decades ago. Most significantly, cholesterol levels fell for the men who developed Alzheimer's prior to their showing Alzheimer's symptoms. The authors suggested that their high cholesterol might have been a protective mechanism against Alzheimer's.

One might wonder why their cholesterol levels fell. There was no mention of statin drugs in the article, but statins would certainly be an effective way to reduce cholesterol levels. The statin industry would like people to believe that high cholesterol is a risk factor for Alzheimer's, and they are quite thrilled that high cholesterol early in life is correlated with Alzheimer's much later. But these results suggest quite the opposite: that blood cholesterol levels are kept high intentionally by the body regulatory mechanisms in an attempt to compensate for the defect. A high concentration will lead to an increase in the rate of delivery to the brain, where it is critically needed to keep the myelin sheath healthy and to promote neuron signaling in the synapses.

Using MRI technology, researchers at UCLA were able to measure the degree of breakdown of myelin in specific regions of the brain [6]. They conducted their studies on over 100 people between 55 and 75 years old, for whom they also determined the associated apoE allele (2, 3, or 4). They found a consistent trend in that apoE-2 had the least amount of degradation, and apoE-4 had the most, in the frontal lobe region of the brain. All of the people in the study were thus far healthy with respect to Alzheimer's. These results show that premature breakdown of myelin sheath (likely due to an insufficient supply of fats and cholesterol to repair it) is associated with apoE-4.

To summarize, I hypothesize that, for the apoE-4 Alzheimer's patients, defective apoE has led to an impaired ability to transport fats and cholesterol from the blood stream, via the astrocytes, into the cerebrospinal fluid. The associated high blood serum cholesterol is an attempt to partially correct for this defect. For the rest of the Alzheimer's patients (the ones without the apoE-4 allele but who also have severely depleted fatty acids in their cerebrospinal fluid), we have to look for another reason why their fatty acid supply chain might be broken.


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Anonymous said...

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