Oxidative stress is a major aspect of Alzheimer disease (AD) pathology. We have investigated the relationship between oxidative stress and neuronal binding of A␤ oligomers (also known as ADDLs). ADDLs are known to accumulate in brain tissue of AD patients and are considered centrally related to pathogenesis. Using hippocampal neuronal cultures, we found that ADDLs stimulated excessive formation of reactive oxygen species (ROS) through a mechanism requiring N-methyl-D-aspartate receptor (NMDA-R) activation. ADDL binding to neurons was reduced and ROS formation was completely blocked by an antibody to the extracellular domain of the NR1 subunit of NMDA-Rs. In harmony with a steric inhibition of ADDL binding by NR1 antibodies, ADDLs that were bound to detergent-extracted synaptosomal membranes co-immunoprecipitated with NMDA-R subunits. The NR1 antibody did not affect ROS formation induced by NMDA, showing that NMDA-Rs themselves remained functional. Memantine, an open channel NMDA-R antagonist prescribed as a memory-preserving drug for AD patients, completely protected against ADDL-induced ROS formation, as did other NMDA-R antagonists. Memantine and the anti-NR1 antibody also attenuated a rapid ADDL-induced increase in intraneuronal calcium, which was essential for stimulated ROS formation. These results show that ADDLs bind to or in close proximity to NMDA-Rs, triggering neuronal damage through NMDA-R-dependent calcium flux. This response provides a pathologically specific mechanism for the therapeutic action of memantine, indicates a role for ROS dysregulation in ADDL-induced cognitive impairment, and supports the unifying hypothesis that ADDLs play a central role in AD pathogenesis. Reactive oxygen species (ROS)4 are minor cytotoxic products of normal mitochondrial metabolism. Approximately 1-2% of the oxygen molecules consumed in electron transport generate species, such as superoxide and hydrogen peroxide (1, 2), mainly through side reactions catalyzed by respiratory complexes I (3) and III (1, 3-5). However, imbalance between mitochondrial ROS production and the intracellular levels of antioxidant defenses leads to oxidative stress, a condition that has been associated with apoptosis (6, 7), inflammation (8), ischemia-reperfusion injury (9, 10), and neurodegenerative diseases (11-15). Several cellular features of the brain suggest that it is highly sensitive to oxidative stress (reviewed in Ref. 16). The brain possesses the highest oxygen metabolic rate of any organ in the body (16), consuming approximately 20% of the total amount of oxygen in the body (17). This enhanced metabolic rate leads to an increased probability that excessive levels of ROS will be produced.In some circumstances, particularly in the brain, even small imbalances can be deleterious. Transient production of ROS plays a role in synaptic signaling, with ROS acting as messenger molecules in the process of long term potentiation (LTP), a well known model for synaptic plasticity and learning (18). On the other hand, abnormally elevated ROS ...

Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with

Defective brain hormonal signaling has been associated with Alzheimer’s disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released upon cleavage of membrane-bound precursor protein FNDC5, also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impaired long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescued synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescued memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuated the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.