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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.