Changes in Brain Glucose Metabolism as a Key to the Pathogenesis of Alzheimer’s Disease

Abstract

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. β-Amyloid precursor protein (β-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 β-region. This process is ATP-dependent. If in SDAT ATP synthesis is critically lowered by a decreased glucose turnover, β-APP cannot be built into the cellular membranes and the β-APP molecule is not split off in the β-region either. The consequence is a generation of β-amyloid from β-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.

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…All these proteins are involved directly or indirectly in the production of ATP in brains (74), and the oxidative modification of glycolytic enzymes likely leads to their inactivation. For example, CK, enolase, PGM1, GAPDH, and ATPase activities are reportedly diminished in AD brain (198,270,363). Glucose is the primary source of energy for the brain, which, though having a relatively small mass as a percentage of body mass, accounts for 20% of glucose metabolism and more than 30% of oxygen consumption.…”

“…Glucose is the primary source of energy for the brain, which, though having a relatively small mass as a percentage of body mass, accounts for 20% of glucose metabolism and more than 30% of oxygen consumption. Glucose metabolism is essential for proper brain function; a minimum interruption of glucose metabolism causes brain dysfunction and memory loss (270). PET scanning shows a consistent pattern of reduced cerebral glucose utilization in AD brain (198).…”

4-Hydroxy-2-Nonenal, a Reactive Product of Lipid Peroxidation, and Neurodegenerative Diseases: A Toxic Combination Illuminated by Redox Proteomics Studies

“…Glucose is the primary source of energy, and glucose metabolism is essential for proper brain function; a minimum interruption of glucose metabolism causes brain dysfunction and memory loss (91,131). Positron emission tomography scanning shows a consistent pattern of reduced cerebral glucose utilization in AD brain (94,166).…”

Energy Inhibition Elevates β-Secretase Levels and Activity and Is Potentially Amyloidogenic in APP Transgenic Mice: Possible Early Events in Alzheimer's Disease Pathogenesis

“…1984; de la Torre, 1999;Matsuda, 2001;Matsuda et al, 2002), and glucose metabolism is reduced in both preclinical and clinical AD (de Leon et al, 1983a,b;Cutler et al, 1985;Rapoport et al, 1991;Meier-Ruge et al, 1994;Reiman et al, 1996;Rapoport, 1999;Small et al, 2000;De Santis et al, 2001;Ibach et al, 2004;Mosconi et al, 2004;Mosconi, 2005), suggesting that impaired energy metabolism may be an early pathological event in SAD. Moreover, cardiovascular diseases appear to increase the risk of AD (Breteler, 2000;Shi et al, 2000;de la Torre, 2004) and the incidence of cerebrovascular atherosclerosis is higher in AD (Roher et al, 2003;Kalback et al, 2004).…”