Mitoenergetic failure in Alzheimer disease

Abstract

Brain cells are highly energy dependent for maintaining ion homeostasis during high metabolic activity. During active periods, full mitochondrial function is essential to generate ATP from electrons that originate with the oxidation of NADH. Decreasing brain metabolism is a significant cause of cognitive abnormalities of Alzheimer disease (AD), but it remains uncertain whether this is the cause of further pathology or whether synaptic loss results in a lower energy demand. Synapses are the first to show pathological symptoms in AD before the onset of clinical symptoms. Because synaptic function has high energy demands, interruption in mitochondrial energy supply could be the major factor in synaptic failure in AD. A newly discovered age-related decline in neuronal NADH and redox ratio may jeopardize this function. Mitochondrial dehydrogenases and several mutations affecting energy transfer are frequently altered in aging and AD. Thus, with the accumulation of genetic defects in mitochondria at the level of energy transfer, the issue of neuronal susceptibility to damage as a function of age and age-related disease becomes important. In an aging rat neuron model, mitochondria are both chronically depolarized and produce more reactive oxygen species with age. These concepts suggest that multiple treatment targets may be needed to reverse this multifactorial disease. This review summarizes new insights based on the interaction of mitoenergetic failure, glutamate excitotoxicity, and amyloid toxicity in the exacerbation of AD.

EstradiolIn VivoRegulation of Brain Mitochondrial Proteome

“…The mitoproteome profile induced by E 2 is reflective of enhanced glycolytic activity (increased aconitase and decreased MDH) coupled with increased glutamatergic turnover (increased glutamate dehydrogenase and glutamate oxaloacetate transaminase-2). The latter can impact generation of neurotoxic free ammonium, as well as direct reduction of excitotoxic free glutamate (Parihar and Brewer, 2007). Consistent with this finding, E 2 has been reported to increase activity of the key glycolytic enzymes hexokinase, phosphofructokinase, and phosphoglycerate kinase in rodent brain (Kostanyan and Nazaryan, 1992).…”

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

“…High levels of glutamate in astrocytes lead to the risk of glutamate being returned to the synaptic cleft if mitochon drial membranes are depolarized, a process that is thought to occur in Alzheimer disease because of reduced energy supplies. 73,74 Taken together, these changes in glutamate transport and conversion to glutamine can lead to increased concentrations of glutamate at the synapse, which can subsequently trigger excitotoxic cell death via NMDA receptor-mediated increase of intracellular Ca 2+ concentrations. 75,76 Elevated Ca 2+ levels lead to neuronal death through a number of known pathways, including increased activation of calpain, 77 release of reactive oxygen species and de polarization of the mitochondrial membrane, which leads to reduced energy metabolism and cytochrome c release.…”

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

“…2). Compared to other organs, bio-energetic production is critical in the brain, since neurons are extremely energy-demanding but have limited glycolysis, making them highly dependent on aerobic oxidative phosphorylation (OXPHOS) [20]. Moreover, the ability of mitochondria to move within cells is also critical in highly polarised cells, such as neurons [21].…”