Brain oxidative energy and related metabolism, neuronal stress, and Alzheimer's disease: a speculative synthesis

Abstract

A reduction in the cerebral metabolic rate of glucose is one of the most predominant abnormalities generally found in the Alzheimer brain, whereas the cerebral metabolic rate of oxygen is diminished only slightly or not at all at the beginning of this dementive disorder. From the cerebral metabolic rates of oxidized glucose and oxygen, the cerebral adenosine triphosphate (ATP) formation rate was calculated in incipient early-onset, incipient late-onset, and stable advanced dementia of the Alzheimer type (DAT). A reduction in ATP formation by various amounts was found, ranging from at least 7% in incipient early-onset DAT, from around 20% in incipient late-onset DAT, and from 35% up to more than 50% in stable advanced dementia. The cerebral diminution in energy availability, along with a loss of functionally important amino acids, ammonia toxicity, supposed membrane damage, dysregulation of Ca2+ homeostasis, and glycogen accumulation in the incipient stages of DAT are assumed to be stress-related abnormalities capable of inducing the formation of heat shock proteins. These events may lead to an enhanced generation of amyloid precursor protein in earlier states of DAT. If abnormally cleaved, amyloid A4 protein may be produced in increased amounts. From the results discussed in this article it is deduced as a speculative synthesis that perturbations in brain oxidative energy and related metabolism may precede the generation of amyloid precursor protein and the formation of plaques in the brain affected by incipient DAT.