A beta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine
ABSTRACT 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.
Article: Therapeutic promise and principles[Show abstract] [Hide abstract]
ABSTRACT: For a number of disease entities, oxidative stress becomes a significant factor in the etiology and progression of cell dysfunction and injury. Therapeutic strategies that can identify novel signal transduction pathways to ameliorate the toxic effects of oxidative stress may lead to new avenues of treatment for a spectrum of disorders that include diabetes, Alzheimer's disease, Parkinson's disease and immune system dysfunction. In this respect, metabotropic glutamate receptors (mGluRs) may offer exciting prospects for several disorders since these receptors can limit or prevent apoptotic cell injury as well as impact upon cellular development and function. Yet the role of mGluRs is complex in nature and may require specific mGluR modulation for a particular disease entity to maximize clinical efficacy and limit potential disability. Here we discuss the potential clinical translation of mGluRs and highlight the role of novel signal transduction pathways in the metabotropic glutamate system that may be vital for the clinical utility of mGluRs.Oxidative medicine and cellular longevity 08/2008; 1(1):1-14. · 3.36 Impact Factor
[Show abstract] [Hide abstract]
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; DOI:10.1007/s12017-015-8355-9 · 3.89 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Cognitive decline and disease progression in different neurodegenerative diseases typically involves synaptic dysfunction preceding the neuronal loss. The synaptic dysfunction is suggested to be caused by imbalanced synaptic plasticity i.e. enhanced induction of long-term depression and concomitantly decreased long-term potentiation accompanied with excess stimulation of extrasynaptic N-Methyl-D-aspartate (NMDA) receptors due to various disturbances in pre- and postsynaptic sites. Recent research has identified neurodegenerative disease-related changes in protein accumulation and aggregation, gene expression, and protein functions, which may contribute to imbalanced synaptic function. Nevertheless, a comprehensive understanding of the mechanisms regulating synaptic plasticity in health and disease is still lacking and therefore characterization of new candidates involved in these mechanisms is needed. Septins, a highly conserved group of guanosine-5'-triphosphate (GTP)-binding proteins, show high neuronal expression and are implicated in the regulation of synaptic vesicle trafficking and neurotransmitter release. In this review, we first summarize the evidence how synaptic dysfunction is related to the pathogenesis of Alzheimer’s, Parkinson’s and Huntington’s disease and frontotemporal lobar degeneration. Then, we discuss different aspects of the potential involvement of the septin family members in the regulation of synaptic function in relation to the pathogenesis of neurodegenerative diseases.Molecular Neurodegeneration 04/2015; 10. DOI:10.1186/s13024-015-0013-z · 5.29 Impact Factor