Thursday, December 17, 2009

7. The Crucial Role of Amyloid-Beta

Amyloid-beta (also known as "abeta") is the substance that forms the famous plaque that accumulates in the brains of Alzheimer's patients. It has been believed by many (but not all) in the research community that amyloid-beta is the principal cause of Alzheimer's, and as a consequence, researchers are actively seeking drugs that might destroy it. However, amyloid-beta has the unique capability of stimulating the production of an enzyme, lactate dehydrogenase, which promotes the breakdown of pyruvate (the product of anaerobic glucose metabolism) into lactate, through an anaerobic fermentation process, with the further production of a substantial amount of ATP.

The lactate, in turn, can be utilized itself as an energy source by some cells, and it has been established that neurons are on the short list of cell types that can metabolize lactate. So I conjecture that the lactate is transported from the astrocyte to a neighboring neuron to enhance its energy supply, thus reducing its dependence on glucose. It is also known that apoE can signal the production of amyloid-beta, but only under certain poorly understood environmental conditions. I suggest those environmental triggers have to do with the internal manufacture of fats and cholesterol as opposed to the extraction of these nutrients from the blood supply. I.e., amyloid-beta is produced as a consequence of environmental oxidative stress due to an inadequate supply of fats and cholesterol from the blood.

In addition to being utilized as an energy source by being broken down to lactate, pyruvate can also be used as a basic building block for synthesizing fatty acids. So anaerobic glucose metabolism, which yields pyruvate, is a win-win-win situation: (1) it significantly reduces the risk of exposure of fatty acids to oxygen, (2) it provides a source of fuel for neighboring neurons in the form of lactate, and (3) it provides a basic building block for fatty acid synthesis. But it depends upon amyloid-beta to work.

Thus, in my view (and in the view of others [28] [20] Amyloid-Beta and Alzheimer's), amyloid-beta is not a cause of Alzheimer's, but rather a protective device against it. The abstract of reference [28] arguing this point of view is reproduced in full in the Appendix. Several variants of a genetic defect associated with amyloid precursor protein (APP), the protein from which amyloid-beta is derived, have now been identified. A defect in this protein, which is associated with an increased risk of early onset Alzheimer's, would likely lead to a reduced ability to synthesize amyloid-beta, which would then leave the brain with a big problem, since both the fuel and the basic building blocks for fatty acid synthesis would be in short supply, while oxygen trekking through the cell to the mitochondria would be exposing whatever fats were being synthesized to oxidation. The cell would likely be unable to keep up with need, and this would lead to a reduction in the number of fatty acids in the Alzheimer's cerebrospinal fluid, a well-established characteristic of Alzheimer's [38].

1 comment:

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