Pathogenesis of Decreased Glucose Turnover and Oxidative Phosphorylation in Ischemic and Trauma‐Induced Dementia of the Alzheimer Type

Meier‐Ruge, W.; Bertoni–Freddari, Carlo

doi:10.1111/j.1749-6632.1997.tb48474.x

Cited by 29 publications

(12 citation statements)

References 67 publications

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“…These findings are also consistent with microarray analyses of aging, incipient AD, and AD human samples and rodent models demonstrating that genes involved in mitochondrial bioenergetics are among those altered early in AD or MCI patients (22,28). Consistent with mitochondrial dysfunction, decreased mitochondrial bioenergetics has been demonstrated to cause amyloid production and nerve cell atrophy (29,30).…”

Section: Discussionsupporting

confidence: 81%

Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

Yao

Irwin

Zhao

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

842

743

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Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (A␤) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of A␤ binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.ABAD ͉ aging ͉ bioenergetics ͉ brain hypometabolism ͉ mitochondria T he essential role of mitochondria in cellular bioenergetics and survival has been well established (1-3). Previous studies have suggested that mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) (1, 4). Alzheimer's pathology is accompanied by a decrease in expression and activity of enzymes involved in mitochondrial bioenergetics, which would be expected to lead to compromised electron transport chain complex activity and reduced ATP synthesis (5). Further, in AD there is a generalized shift from glycolytic energy production toward use of an alternative fuel, ketone bodies. This is evidenced by a 45% reduction in cerebral glucose utilization in AD patients (6), which is paralleled by decrease in the expression of glycolytic enzymes coupled to a decrease in the activity of the pyruvate dehydrogenase (PDH) complex (5). Patients with incipient AD exhibit a utilization ratio of 2:1 glucose to alternative fuel, whereas comparably aged controls exhibit a ratio of 29:1, whereas young controls exclusively use glucose as with a ratio of 100:0 ratio (7). In addition to t...

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Section: Discussionsupporting

confidence: 81%

Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

Yao

Irwin

Zhao

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

842

743

View full text Add to dashboard Cite

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“…An increase in the formation of amyloid precursor protein (APP) has been observed immunohistochemically in the spinal cord after a severe form of metabolic stress [19]. APP has been shown to inactivate phosphofructokinase, the key glycolytic enzyme, resulting in decreased glucose turnover in CNS disorders [24]. Such a scenario could explain the unchanged glucose levels of the present investigation.…”

Section: Discussionsupporting

confidence: 55%

Regional Spinal Cord Blood Flow and Energy Metabolism in Rats after Laminectomy and Acute Compression Injury

Mautes

Schröck

Nacimiento

et al. 2000

European Journal of Trauma

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Many data are available concerning spinal cord blood flow (SCBF) and metabolism on various models and timing after spinal cord injury, however, detailed information on their exact relationship in the same injury model is lacking. This relationship is a crucial factor in the understanding of the pathophysiology of spinal cord trauma.Rats were subjected to lumbar laminectomy or lumbar spinal cord compression trauma. 3 hours later, changes in SCBF were evaluated autoradiographically and changes in ATP, glucose and lactate levels were analyzed using substrate-specific bioluminescence techniques. Measurements were performed at the lesion site (segment L4), adjacent segments (L3 and L5) and at remote thoracic segments (Th8 to Th9).Laminectomy alone did not change SCBF, both in thoracic and lumbar segments. In contrast, ATP levels were significantly reduced and lactate levels were increased at the lesion site and in adjacent lumbar segments at 3 hours after laminectomy, whereas glucose levels were not significantly changed. In animals subjected to additional compression trauma, SCBF was significantly reduced in segments L3, L4 and L5 paralleled by a significant ATP reduction and lactate increase. Glucose levels did not differ significantly from controls 3 hours after compression injury. This metabolic profile was also reflected in the remote thoracic segments. In contrast, SCBF was not reduced in thoracic segments of traumatized animals.The observation that ATP was already significantly reduced and lactate increased in laminectomized segments and in remote thoracic regions after trauma signals that metabolic changes are sensitive indicators to spinal stress. The fact that posttraumatic metabolic profile differs from the pattern of hemodynamic and metabolic changes induced by ischemia, suggests posttraumatic mediators may be involved in the different regulation of the energy producing machinery.

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“…Excessive amounts of glutamate released in the course of ischemia induce the development of acute excitotoxicity in the СА1 area of the hippocampus. Excessive glutamate, in turn, potentiates the synthesis of APP (precursor of amyloid) [26]. The latter protein is a highly sensitive indicator of disorders in axonal transport; after ischemic damage, APP is stored in injured but still viable neurons [27,28].…”

Section: Discussionmentioning

confidence: 99%

Behavioral reactions of gerbils and structural alterations in their hippocampus after cerebral ischemia-reperfusion

et al. 2007

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We studied changes in behavior of Mongolian gerbils (Meriones unguiculatus) after ischemia-reperfusion of the brain (7-min-long occlusion of both arteriae carotis) and structural alterations in the hippocampus of such animals. Behavioral manifestations were observed under conditions of the open field test within 7 days of the postischemic period; immunofluorescent staining of brain sections with antibodies against specific proteins of neurons and glial cells was used. Motor hyperactivity reaching its maximum a day after ischemization and gradually decreasing within the postocclusion period was found in ischemized animals. On the 7th day, the level of locomotor activity in experimental gerbils was practically equal to that in the control group. In contrast, a postischemic decrease in the duration of episodes of resting was preserved for a longer time. A week after ischemia-reperfusion, intense delayed neuronal death and activation of glial cells were observed in the СА1 hippocampal area. Thus, cerebral ischemia-reperfusion results in significant transient disorders of behavioral phenomena in gerbils; at the same time, a clear correlation is observed between structural changes of neurons and the level of reactivity of glial cells in the hippocampus. These events can be significant aspects of the dynamics of postischemic damage to the above structure.

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Pathogenesis of Decreased Glucose Turnover and Oxidative Phosphorylation in Ischemic and Trauma‐Induced Dementia of the Alzheimer Type

Cited by 29 publications

References 67 publications

Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

Regional Spinal Cord Blood Flow and Energy Metabolism in Rats after Laminectomy and Acute Compression Injury

Behavioral reactions of gerbils and structural alterations in their hippocampus after cerebral ischemia-reperfusion

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