The Significance of Glucose Turnover in the Brain in the Pathogenetic Mechanisms of Alzheimer's Disease

Abstract

This paper presents a comprehensive survey of the pathogenesis and pathophysiology of Alzheimer's disease (AD). Two mechanisms are of etiological importance in the development of a degenerative dementing brain disease: 1. Lesions in the mitochondrial genome that are caused by free radicals. Primary degenerative AD is characterized by a tendency to acquire random lesions within mitochondrial DNA that are produced by free radicals. The consequence of these lesions is a decrease in glucose turnover and a decline in oxidative phosphorylation. Point mutations on chromosome 21 are hypothesized to increase the susceptibility of mitochondrial DNA to lesions created by free radicals. 2. Ischemic brain lesions as well as traumatic brain damage cause an increase in the release of excitotoxic amino acids (glutamate, aspartate, etc.). These neurotransmitters increase CA(+2) influx into the nerve cell and significantly lower energy production. From a pathogenetic point of view, AD is characterized by a decrease in glucose turnover in the brain. The progression of AD can be monitored by F18- deoxyglucose PET studies. This technique also allows the recognition of patients who are prone to develop AD. The actual development of a cognitive deficit is a threshold phenomenon that occurs if glucose turnover in the hippocampus or temporoparietal cortex drops below a critical level of about 40% of the level of age-matched controls. The low glucose turnover in AD causes a cholinergic deficit by decreasing the synthesis of AcCoA, which is used by choline acetyltransferase in the acetylation of choline to acetylcholine. The decrease in glucose turnover also reduces oxidative phosphorylation. The resulting decrease in ATP triggers the hyperphosphorylation of tau protein by activating protein kinase 40erk. The hyperphosphorylation leads to the development of paired helical filaments. The generation of beta amyloid and the loss of neuronal synapses are also caused by a decrease in oxidative phosphorylation, since beta amyloid precursor proteins are not inserted into the membranes of nerve cells in the absence of a sufficient amount of ATP. This results in the generation of intact beta amyloid molecules and leads to amyloidosis in the brains of patients with Alzheimer's disease.

Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease

“…Furthermore, vascularmediated depression of cerebral glucose and oxygen metabolism correlate positively with the severity of AD. 50,51 Moreover, these metabolic disturbances appear to precede neurodegeneration and overt cognitive impairment in AD. [52][53][54] Progressive atherosclerotic and small vessel disease chronically limit cerebral oxygen delivery while altering endothelial exchange dynamics.…”

Reevaluating the Role of Vascular Changes in the Differential Diagnosis of Alzheimer’s Disease and Vascular Dementia

“…Several etiopathogenetic hypotheses have been proposed such as altered glucose transport across pathological microvessels [95], a decrease in neuronal uptake of glucose [96], and decreased oxidation of glucose secondary to mitochondrial DNA damage [97,98], but none of these has been confirmed. Importantly, long-term decrements in glucose and oxygen consumption in diabetic patients result in several neuropathological changes such as neuronal loss, gliosis and SP formation [99].…”

Insulin Dysfunction InducesIn VivoTau Hyperphosphorylation through Distinct Mechanisms

“…Compared with age-matched controls, AD patients show reduced CSF insulin (Craft et al, 1998), impaired insulin-like signal transduction (Frolich et al, 1999), decreased brain insulin and insulin-like growth factor I expression and function (Rivera et al, 2005), and reduced glucose metabolism (Mosconi, 2005). From these observations, it was suggested that brain insulin signaling dysfunction and the possible consequent reduction in glucose metabolism are crucial in the genesis of AD (Meier-Ruge and Bertoni-Freddari, 1996;Salehi and Swaab, 1999;Heininger, 2000;Hoyer, 2000Hoyer, , 2002Gasparini et al, 2002;Watson and Craft, 2003). Insulin dysfunction is a feature of DM, and, although AD and DM were first found to be strongly associated or mutually exclusive in a series of conflicting epidemiological studies (Finch and Cohen, 1997), many longitudinal population-based studies detected higher AD incidences rates in diabetic patients (Biessels et al, 2006).…”