Neurodegenerative Disease Alzheimer’s Disease Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease Paula I Moreira Researcher, Faculty of Medicine and Centre for Neuroscience and Cell Biology, University of Coimbra


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 peripherally.7–10


but also occurs before Aβ plaque formation,4


Moreover, it has been shown that oxidative damage 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


© TOUCH BRIEFINGS 2010


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.


Mitochondria perform pivotal biochemical functions necessary for homeostasis and are arbiters of cell death and survival, in addition to being a main source of adenosine triphosphate (ATP). They represent a convergence point for death signals triggered by both extracellular and intracellular cues. As such, the mitochondria sit at a strategic position in the hierarchy of cellular organelles to either promote the healthy life of the cell or to terminate it.11–12


Mitochondria are essential for neuronal


function because the limited glycolytic capacity of neurons makes them highly dependent on aerobic oxidative phosphorylation (OXPHOS) for their energetic needs.13


However, OXPHOS is a major source of toxic


endogenous free radicals, including hydrogen peroxide (H2O2), hydroxyl (•OH) and superoxide (O2-•) radicals, which are products of normal cellular respiration. When the electron transport chain (ETC) is inhibited, electrons accumulate in complex I and co-enzyme Q where


they can be donated directly to molecular oxygen to yield O2-•, which can be further detoxified by the mitochondrial manganese superoxide


dismutase (MnSOD) producing H2O2, which in turn can be converted to H2O by glutathione peroxidase (GPx). However, O2-• in the presence of nitric oxide (NO•), formed during the conversion of arginine to citrulline by nitric oxide synthase (NOS), can lead to the formation of


peroxynitrite (ONOO-). Furthermore, H2O2 in the presence of reduced transition metals can be converted to the toxic product •OH via Fenton and/or Haber–Weiss reactions.


It is well recognised that reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a dual role since they can be either


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