Mitochondrial- and endoplasmic reticulum-associated oxidative stress in Alzheimer's disease: from pathogenesis to biomarkers

Abstract

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting several million of people worldwide. Pathological changes in the AD brain include the presence of amyloid plaques, neurofibrillary tangles, loss of neurons and synapses, and oxidative damage. These changes strongly associate with mitochondrial dysfunction and stress of the endoplasmic reticulum (ER). Mitochondrial dysfunction is intimately linked to the production of reactive oxygen species (ROS) and mitochondrial-driven apoptosis, which appear to be aggravated in the brain of AD patients. Concomitantly, mitochondria are closely associated with ER, and the deleterious crosstalk between both organelles has been shown to be involved in neuronal degeneration in AD. Stimuli that enhance expression of normal and/or folding-defective proteins activate an adaptive unfolded protein response (UPR) that, if unresolved, can cause apoptotic cell death. ER stress also induces the generation of ROS that, together with mitochondrial ROS and decreased activity of several antioxidant defenses, promotes chronic oxidative stress. In this paper we discuss the critical role of mitochondrial and ER dysfunction in oxidative injury in AD cellular and animal models, as well as in biological fluids from AD patients. Progress in developing peripheral and cerebrospinal fluid biomarkers related to oxidative stress will also be summarized.

Figure 1

Sources of reactive oxygen species in Alzheimer's disease. Extracellular accumulation of Aβ may direct or indirectly alter NMDARs-mediated glutamatergic neurotransmission with concomitant cytosolic Ca²⁺ increase and impaired synaptic activity. Excitotoxic increase in glutamatergic neurotransmission may activate extrasynaptic NMDARs leading to a massive increase in the intracelular Ca²⁺, which is rapidly taken up by mitochondria and ER. Mitochondria Ca²⁺ overload promotes the generation of ROS. Additionally, the ER may also promote ROS production. Decreased PDI activity may lead to polyubiquitinated proteins accumulation, which may thus induce the UPR, mediated by IRE1α, PERK, and ATF6 pathways. In order to cope with the need to balance disulfide bond formation, the activity of ERO1α is increased leading to the production of ROS that are able to directly attack and affect IP₃R function. Since the ER and the mitochondria are in close proximity, the Ca²⁺ released from the ER, through the IP₃R, can then enter directly into mitochondria, through the VDAC or the MCU, leading to the increase in mitochondrial Ca²⁺ content, inducing mitochondrial ROS production. As a result of prolonged ER stress, CHOP may induce ERO1α upregulation or activate the enzyme CaMKII, which can further activate NOX, localized at the plasma membrane, enhancing cytosolic ROS production. As a consequence, protective antioxidant defenses such as GSH are depleted. In addition, Nrf2, which normally translocates to the nucleus where it activates the antioxidant response element, may be retained in the cytosol.