Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine

Northwestern University, Evanston, Illinois, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2007; 282(15):11590-601. DOI: 10.1074/jbc.M607483200
Source: PubMed


Oxidative stress is a major aspect of Alzheimer disease (AD) pathology. We have investigated the relationship between oxidative stress and neuronal binding of Abeta 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.

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    • "Oxidative Medicine and Cellular Longevity (CICR), then produces altered surface expression and dysregulation of receptor function, excitotoxicity, dendritic spine retraction, and elimination [4] [5] [6]. Aí µí»½ also plays a crucial role in inducing neuronal oxidative stress [7] [8]. Aí µí»½-mediated mitochondrial oxidative stress causes hyperphosphorylation of tau in AD brains [8] [9] [10]. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia. The pathological hallmarks of AD are amyloid plaques [aggregates of amyloid-beta (Aβ)] and neurofibrillary tangles (aggregates of tau). Growing evidence suggests that tau accumulation is pathologically more relevant to the development of neurodegeneration and cognitive decline in AD patients than Aβ plaques. Oxidative stress is a prominent early event in the pathogenesis of AD and is therefore believed to contribute to tau hyperphosphorylation. Several studies have shown that the autophagic pathway in neurons is important under physiological and pathological conditions. Therefore, this pathway plays a crucial role for the degradation of endogenous soluble tau. However, the relationship between oxidative stress, tau protein hyperphosphorylation, autophagy dysregulation, and neuronal cell death in AD remains unclear. Here, we review the latest progress in AD, with a special emphasis on oxidative stress, tau hyperphosphorylation, and autophagy. We also discuss the relationship of these three factors in AD.
    Oxidative Medicine and Cellular Longevity 07/2015; 2015:352723. DOI:10.1155/2015/352723 · 3.36 Impact Factor
    • ") , and downregulation of AMPAR subunits prevents AβO binding to neurons ( Zhao et al . , 2010 ) . We have found that knockdown of NMDA receptors by a viral vector - mediated antisense approach ( Decker et al . , 2010a ) or treatment of neurons with an antibody against the extracellular domain of the constitutive NR1 subunit of NMDA receptors ( De Felice et al . , 2007 ) block binding of AβOs to neuronal surface membranes . At the same time , however , presence of NMDA receptors on the neuronal surface is not sufficient for binding of AβOs to hippocampal neurons ( Decker et al . , 2010a ) . These results suggest that NMDA receptors are an integral component , likely an organizer of a receptor complex "
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    ABSTRACT: Alzheimer’s disease (AD) is the most common form of dementia in the elderly, and affects millions of people worldwide. As the number of AD cases continues to increase in both developed and developing countries, finding therapies that effectively halt or reverse disease progression constitutes a major research and public health challenge. Since the identification of the amyloid-b peptide (Ab) as the major component of the amyloid plaques that are characteristically found in AD brains, a major effort has aimed to determine whether and how Ab leads to memory loss and cognitive impairment. A large body of evidence accumulated in the past 15 years supports a pivotal role of soluble Ab oligomers (AbOs) in synapse failure and neuronal dysfunction in AD. Nonetheless, a number of basic questions, including the exact molecular composition of the synaptotoxic oligomers, the identity of the receptor(s) to which they bind, and the signaling pathways that ultimately lead to synapse failure, remain to be definitively answered. Here, we discuss recent advances that have illuminated our understanding of the chemical nature of the toxic species and the deleterious impact they have on synapses, and have culminated in the proposal of an Ab oligomer hypothesis for Alzheimer’s pathogenesis. We also highlight outstanding questions and challenges in AD research that should be addressed to allow translation of research findings into effective AD therapies.
    Frontiers in Cellular Neuroscience 05/2015; 9. DOI:10.3389/fncel.2015.00191 · 4.29 Impact Factor
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    • "In accordance with the view of facilitated excitatory neurotransmission, Wu et al. (1995) reported a facilitation of NMDA receptor-dependent neurotransmission by Ab. Finally, supporting the hypothesis of synaptic dysfunction, several groups have recently reported that Ab 42 oligomers impair NMDA receptor function in vitro (Lacor et al. 2007; De Felice et al. 2007; Shankar et al. 2007; Snyder et al. 2005). Using a different preparation , Kelly and Ferreira showed that Ab 42 oligomers cause synaptic dysfunction by depletion of the readily releasable pool of presynaptic vesicles (Kelly and Ferreira 2007). "
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    ABSTRACT: Cognitive and behavioral acts go along with highly coordinated spatiotemporal activity patterns in neuronal networks. Most of these patterns are synchronized by coherent membrane potential oscillations within and between local networks. By entraining multiple neurons into a common time regime, such network oscillations form a critical interface between cellular activity and large-scale systemic functions. Synaptic integrity is altered in neurodegenerative diseases, and it is likely that this goes along with characteristic changes of coordinated network activity. This notion is supported by EEG recordings from human patients and from different animal models of such disorders. However, our knowledge about the pathophysiology of network oscillations in neurodegenerative diseases is surprisingly incomplete, and increased research efforts are urgently needed. One complicating factor is the pronounced diversity of network oscillations between different brain regions and functional states. Pathological changes must, therefore, be analyzed separately in each condition and affected area. However, cumulative evidence from different diseases may result, in the future, in more unifying "oscillopathy" concepts of neurodegenerative diseases. In this review, we report present evidence for pathological changes of network oscillations in Alzheimer's disease (AD), one of the most prominent and challenging neurodegenerative disorders. The heterogeneous findings from AD are contrasted to Parkinson's disease, where motor-related changes in specific frequency bands do already fulfill criteria of a valid biomarker.
    Neuromolecular medicine 04/2015; 17(3). DOI:10.1007/s12017-015-8355-9 · 3.68 Impact Factor
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