SOURCES AND EFFECTS OF REACTIVE OXYGEN INTERMEDIATES IN THE BRAIN

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Del Rio Hortega in 1919 was the first person to recognize the importance of microglia. They are the brain macrophages or phagocytes, which also release reactive oxygen species. Their function is to get rid of unwanted cellular debris and also to kill invading microorganisms. An oxygen burst is generated by the hexose monophosphatase shunt producing the superoxide anion by the NADPH oxidase at the membrane. Phorbol myristate acetate (PMA) acts directly on this mechanism. We investigated the effect of beta amyloid (A-beta) on the production of superoxide anion of activated microglia. A-beta (1-40) is derived from the amyloid precursor protein, which contains about 700 amino acids. The cysteine rich section contains a site which can reduce cupric ions to cuprous ions. A-beta has an extracellular domain as well as a membrane domain. We experimented on activated hamster microglia and human monocyte derived macrophages with PMA, and found that additional exposure to A-beta (1-40) produced only a small quantity of superoxide anion. However, when the microglia were primed or pretreated with A-beta followed by PMA activation, there was a larger increase in superoxide anion production. Without PMA, the superoxide production was reduced to the value obtained in the presence of A-beta (1-40), which was greater than the non-primed and non-stimulated case. The conclusion is that there is another site responsible for the superoxide production. Perhaps this site is the mitochondrion. In Alzheimer's disease, A-beta (1-40) is located in the plaque periphery, where it causes the resting microglia found in plaques to produce damaging reactive oxygen species, which can attack the most vulnerable part of the nervous system, the synapses. Microglia are not able to destroy the plaques because they are composed of beta pleated sheets, which are only soluble in formic acid.