Changes in brain glucose metabolism as a key to the pathogenesis of Alzheimer's disease.
The article discusses some aspects demonstrating that a decrease in acetylcholine synthesis in senile dementia of the Alzheimer type (SDAT) is a consequence of the strong decline in glucose turnover in the brain. This becomes obvious by the fact that acetylcoenzyme A, the key substrate of acetylcholine synthesis, is exclusively synthesized in the glycolytic pathway in the brain. This means that a single molecule of glucose synthesizes only two molecules of acetylcoenzyme A but 38 molecules of ATP. This is critically changed if glucose metabolism of the brain decreases in SDAT. beta-Amyloid precursor protein (beta-APP) of chromosome 21 is a regular protein of repair of any cellular membrane in the body. It is integrated into the cellular membranes and split off by proteases in the beta-region. This process is ATP-dependent. If in SDAT ATP synthesis is critically lowered by a decreased glucose turnover, beta-APP cannot be built into the cellular membranes and the beta-APP molecule is not split off in the beta-region either. The consequence is a generation of beta-amyloid from beta-APP fragments, which are progressively accumulated in senile plaques and vascular walls. The missing repair of cellular membranes and synapses in the brain results in nerve cell atrophy and a shrinkage of the brain. It is concluded that the cholinergic deficit, nerve cell atrophy and the amyloid accumulation in the brain are secondary phenomena caused by the 50-70% decline of glucose metabolism in SDAT.
Department of Pathology, University Medical School of Basel, Switzerland.
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Meier-Ruge
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Bertoni-Freddari
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Iwangoff
D000105:Acetyl Coenzyme A / Q000096:biosynthesis; D000109:Acetylcholine / Q000096:biosynthesis; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002891:Chromosomes, Human, Pair 21; D005947:Glucose / Q000378:metabolism*; D006801:Humans
D016564:Amyloid beta-Protein Precursor; D000105:Acetyl Coenzyme A; D000255:Adenosine Triphosphate; D005947:Glucose; D000109:Acetylcholine