Oxidative Stress, Synaptic Dysfunction, and Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.

Keywords: Alzheimer’s disease; amyloid-β; antioxidants; caloric restriction; exercise; mitochondria; mitohormesis; neurotransmission; oxidative stress; synaptic function; tau protein.

Fig.1

ROS production in mitochondria during oxidative phosphorylation and antioxidant mechanisms. Complex I and complex III of the mitochondrial electron transport chain are the major sites of superoxide anion (O₂^–) production during aerobic respiration. O₂^– is converted to H₂O₂ by MnSOD or CuZnSOD in the intermembrane mitochondrial space. H₂O₂ is further reduced to water by detoxifying enzymes glutathione peroxidase (GPX) or catalase. GPX uses reduced glutathione (GSH) as the reductant, and the resulting oxidized glutathione reacts with another glutathione molecule to form glutathione disulfide (GSSG), which is restored to GSH by the enzyme glutathione reductase (GR). These reactions occur in mitochondrial matrix.

Fig.2

Molecular targets of ROS. While multiple sites in the cell can contribute to ROS production, uncontrolled ROS generation in mitochondria could impair a major source of energy in the cell resulting in detrimental consequences to the whole cellular environment. Intermediate levels of ROS can gradually affect multiple cellular functions including loss of synaptic activity, while critically damaged mitochondria can trigger a release of cytochrome c activating apoptosis.

Fig.3

Genetic and environmental risk factors contribute to the development of late onset sporadic AD. With age, increased mitochondrial dysfunction and ROS production could initiate a vicious cycle where multiple systems and mechanisms affected by ROS exacerbate ROS production, accelerating cellular damage, and leading to synaptic dysfunction.

Fig.4

Structure of a synapse. Left: synapse between two neurons observed in the brain tissue of a wild type C57/Bl6 mouse using transmission electron microscopy (generated in Dr. Trushina laboratory [231]). An arrow indicates electron dense plasma membrane at the synapse. Presynaptic neurons contain a large number of synaptic vesicles (#). Both presynaptic and postsynaptic neurons have mitochondria at the site of synapse (*), which are delivered along the microtubule tracks (indicated with arrows). Scale bar, 0.5 μm. Right: a simplified cartoon of a synapse. Glutamate (blue spheres) released from the presynaptic neuron in a voltage dependent manner, activates the NMDA glutamate receptors present on pre- and postsynaptic neurons. These include AMPA (orange) and NMDA (green) receptors among others. Glutamate is cleared from the synaptic cleft primarily by the glial cells transporters (GLT-1). It is then recycled to neurons, repackaged into synaptic vesicles, and used in another synapse. An inadequate glutamate clearance could lead to the spillover and activation of extrasynaptic NMDA receptors. Memantine is believed to prevent this particular activation. Excessive entry of Ca²⁺ into presynaptic neuron (red spheres) could damage synaptic mitochondria leading to ROS production, altered synaptic transmission and neuronal dysfunction. This phenomenon is called excitotoxicity. Note that mitochondria are delivered to the site of synapse along the Tau-containing microtubule tracks. Destabilization of microtubules could affect mitochondrial localization and energy supply required for proper synaptic function.