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.
SourceAvailable from: Danielle Beckman[Show abstract] [Hide abstract]
ABSTRACT: Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α-P). AβOs further induced eIF2α-P and activated pro-inflammatory IKKβ/NF-κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-α (TNF-α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.EMBO Molecular Medicine 01/2015; 7(2). DOI:10.15252/emmm.201404183 · 8.25 Impact Factor
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 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