Alzheimer's disease: roles for mitochondrial damage, the hydroxyl radical, and cerebrospinal fluid deficiency of melatonin.

A deficiency of cerebrospinal fluid melatonin is postulated to be critical for the development of Alzheimer's disease. Some melatonin is normally secreted directly into the fluid inducing higher levels than in simultaneously sampled blood. Melatonin is carried into the ventricular system via choroid plexus portals. The neurohormone is a potent antioxidant that passes through cell membranes with ease and is concentrated in mitochondria. Neural tissue in contact with the ventricular system will have high levels of cellular melatonin. In Alzheimer's disease, inadequate melatonin allows hydroxyl radicals produced by mitochondrial complex IV to damage mitochondria and initiate a cascade of oxygen radicals that causes the neuropathological changes in Alzheimer's disease. Results from initial therapeutic trials of melatonin in Alzheimer's disease patients have demonstrated improved function, decreased 'sundowning', improved sleep, and a significant slowing of the progression of the disease.