Neurotoxicity Research

, 5:385 | Cite as

Coupled reductions in brain oxidative phosphorylation and synaptic function can be quantified and staged in the course of Alzheimer disease



In vivo, post-mortem and biopsy data suggest that coupled deelines occur in brain synaptic activity and brain energy consumption during the evolution of Alzheimer disease. In the first stage of these declines, changes in synaptic structure and function reduce neuronal energy demand and lead to potentially reversible downregulation of oxidative phosphorylation (OXPHOS) within neuronal mitochondria. At this stage, measuring brain glucose metabolism or brain blood flow in patients, using positron emission tomography (PET), shows that the brain can be almost normally activated in response to stimulation. Thus, therapy at this stage should be designed to re-establish synaptic integrity or prevent its further deterioration. As disease progresses, neurofibrillary tangles with abnormally phosphorylated tau protein accumulate within neuronal cytoplasm, to the point that they co-opt the nonphosphorylated tau necessary for axonal transport of mitochondria between the cell nucleus and the synapse. In this second stage, severe energy depletion and other pathological processes associated with irreversibly downregulated OXPHOS lead to cell death, and the brain cannot normally respond to functional stimulation.


Alzheimer disease Cytochrome oxidase Positron emission tomography Brain Energy Metabolism Oxidative phosphorylation Mitochondria Activation Glucose Blood flow Synapse Neurofibrillary tangles Senile plaques mRNA 


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© FP Graham Publishing Co 2003

Authors and Affiliations

  1. 1.Brain Physiology and Metabolism SectionsNational Institutes of HealthBethesdaUSA

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