Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease
Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease
European Neurological Review, 2010; 5(1): 17–21
Abstract
Oxidative stress and mitochondrial dysfunction are important issues in understanding the pathogenesis of Alzheimer’s disease (AD). Mitochondria are pivotal in controlling cell life and death not only by producing adenosine triphosphate and sequestering calcium but also by generating reactive oxidative species and serving as repositories for proteins that regulate the intrinsic apoptotic pathway. Perturbations in the physiological function of mitochondria inevitably disturb cell function, sensitise cells to neurotoxic insults and may initiate cell death, all significant phenomena in the pathogenesis of AD. This article discusses evidence supporting the notion that mitochondrial dysfunction and oxidative stress are intimately involved in AD pathophysiology.
Keywords
Alzheimer’s disease, cell death, mitochondria, neurodegeneration, oxidative stress
Disclosure: The author has no conflicts of interest to declare.
Received: 22 April 2010 Accepted: 21 June 2010 Citation: European Neurological Review, 2010;5(1):17–21
Correspondence: Paula I Moreira, Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal. E: venta@ci.uc.pt
Alzheimer’s disease (AD) is the most common form of dementia and affects millions of people worldwide. The disorder is characterised by severe memory loss, with episodic memory being particularly impaired during the initial phases. Most AD cases occur sporadically, although inheritance of certain susceptibility genes enhances the risk. Familial AD represents the minority of AD cases and is caused by mutations in genes encoding for the amyloid β precursor protein (APP), presenilin 1 (PS1) or presenilin 2 (PS2). Two pathological hallmarks are observed in AD brains at autopsy: intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques (SPs) in the neocortex, hippocampus and other subcortical regions essential for cognitive function (see Figure 1). NFTs are formed from paired helical filaments composed of neurofilaments and hyperphosphorylated tau protein. In turn, plaque cores are formed mostly from the deposition of amyloid β (Aβ) peptide that results from the cleavage of APP.
The literature shows that mitochondrial dysfunction and oxidative stress play important roles in the early pathology of AD.1–3 Indeed, there are strong indications that oxidative stress occurs prior to the onset of symptoms in AD and oxidative damage is found not only in the vulnerable regions of the brain affected in disease,4–6 but also peripherally.7–10 Moreover, it has been shown that oxidative damage occurs before Aβ plaque formation,4 supporting a causative role of mitochondrial dysfunction and oxidative stress in AD. This review is devoted to discussing evidence showing that mitochondrial dysfunction and oxidative stress are intimately involved in AD pathophysiology.
The Dual Role of Brain Mitochondria
Although the brain represents only 2% of bodyweight, it receives 15% of cardiac output and accounts for 20% of total body oxygen consumption. This energy requirement is largely driven by neuronal demand for energy to maintain ion gradients across the plasma membrane, which is critical for the generation of action potentials. This intense energy requirement is continuous; even brief periods of oxygen or glucose deprivation result in neuronal death.
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Alzheimer’s disease, cell death, mitochondria, neurodegeneration, oxidative stress
