The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

Peters, Christian; Sepúlveda, Fernando J.; Fernández-Pérez, Eduardo J.; Peoples, Robert W.; Aguayo, Luis G.

doi:10.3233/jad-160170

Cited by 14 publications

(8 citation statements)

References 49 publications

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“…One possibility is that channel formation is dependent on bilayer composition found only within a third of patches pulled. Perhaps membrane proteins can modulate channel formation (52). Others have highlighted the importance of membrane composition for effective A␤ insertion and perforation of model lipid membranes, specifically pointing to GM1 and cholesterol as key mediators of membrane interaction and perforation (16,53,54).…”

Section: Discussionmentioning

confidence: 99%

Ion Channel Formation by Amyloid-β42 Oligomers but Not Amyloid-β40 in Cellular Membranes

Bode

Baker

Viles

2017

Journal of Biological Chemistry

180

227

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A central hallmark of Alzheimer's disease is the presence of extracellular amyloid plaques chiefly consisting of amyloid-β (Aβ) peptides in the brain interstitium. Aβ largely exists in two isoforms, 40 and 42 amino acids long, but a large body of evidence points to Aβ(1-42) rather than Aβ(1-40) as the cytotoxic form. One proposed mechanism by which Aβ exerts toxicity is the formation of ion channel pores that disrupt intracellular Ca homeostasis. However, previous studies using membrane mimetics have not identified any notable difference in the channel forming properties between Aβ(1-40) and Aβ(1-42). Here, we tested whether a more physiological environment, membranes excised from HEK293 cells of neuronal origin, would reveal differences in the relative channel forming ability of monomeric, oligomeric, and fibrillar forms of both Aβ(1-40) and Aβ(1-42). Aβ preparations were characterized with transmission electron microscopy and thioflavin T fluorescence. Aβ was then exposed to the extracellular face of excised membranes, and transmembrane currents were monitored using patch clamp. Our data indicated that Aβ(1-42) assemblies in oligomeric preparations form voltage-independent, non-selective ion channels. In contrast, Aβ(1-40) oligomers, fibers, and monomers did not form channels. Ion channel conductance results suggested that Aβ(1-42) oligomers, but not monomers and fibers, formed three distinct pore structures with 1.7-, 2.1-, and 2.4-nm pore diameters. Our findings demonstrate that only Aβ(1-42) contains unique structural features that facilitate membrane insertion and channel formation, now aligning ion channel formation with the differential neurotoxic effect of Aβ(1-40) and Aβ(1-42) in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Ion Channel Formation by Amyloid-β42 Oligomers but Not Amyloid-β40 in Cellular Membranes

Bode

Baker

Viles

2017

Journal of Biological Chemistry

180

227

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“…However, a number of indications propose that Aβ causes extra-synaptic space glutamate level elevation that consequences in ligand gated excitatory ion channels NMDARs overstimulation and finally leading to cell death as well as synaptic loss 186 , 187 . Huperzine A reduces the glutamate excite-toxicity via acting as NMDA receptor antagonist and minimize the level of synaptic loss along with neuronal cell death 188 . As the brain derived neurotropic factor (BDNF) is crucially important in memory and learning process, because it regulates synaptic plasticity, neuronal differentiation, axonal sprouting, as well as long-term potentiation (LTP) 189 .…”

Section: Huperzine Amentioning

confidence: 99%

Role of Plant Derived Alkaloids and Their Mechanism in Neurodegenerative Disorders

et al. 2018

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Neurodegenerative diseases are conventionally demarcated as disorders with selective loss of neurons. Conventional as well as newer molecules have been tested but they offer just symptomatic advantages along with abundant side effects. The discovery of more compelling molecules that can halt the pathology of these diseases will be considered as a miracle of present time. Several synthetic compounds are available but they may cause several other health issues. Therefore, natural molecules from the plants and other sources are being discovered to replace available medicines. In conventional medicational therapies, several plants have been reported to bestow remedial effects. Phytochemicals from medicinal plants can provide a better and safer alternative to synthetic molecules. Many phytochemicals have been identified that cure the human body from a number of diseases. The present article reviews the potential efficacy of plant-derived alkaloids, which possess potential therapeutic effects against several NDDs including Alzheimer's disease (AD), Huntington disease (HD), Parkinson's disease (PD), Epilepsy, Schizophrenia, and stroke. Alkaloids include isoquinoline, indole, pyrroloindole, oxindole, piperidine, pyridine, aporphine, vinca, β-carboline, methylxanthene, lycopodium, and erythrine byproducts. Alkaloids constitute positive roles in ameliorating pathophysiology of these illnesses by functioning as muscarinic and adenosine receptors agonists, anti-oxidant, anti-amyloid and MAO inhibitors, acetylcholinestrase and butyrylcholinesterase inhibitor, inhibitor of α-synuclein aggregation, dopaminergic and nicotine agonist, and NMDA antagonist.

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“…Single stacks of optical sections in the z-axis (1 µm) were acquired, and dual-color immunofluorescent images were captured in simultaneous two-channel mode. The quantification of the fluorescence intensity and number of clusters associated with membrane receptors was carried out off-line using ImageJ software (NIH, Bethesda, MD, USA), using previously reported plug-ins and protocols 62 . Briefly, for each cell analyzed, the relative fluorescence units (URF) of the red channel were obtained by averaging 3 zones with areas of 100 μm 2 .…”

Section: Electrophysiologymentioning

confidence: 99%

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

Moraga-Cid

Martín

Lara

et al. 2020

Sci Rep

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Glycine receptors (GlyRs) are anion-permeable pentameric ligand-gated ion channels (pLGICs). The GlyR activation is critical for the control of key neurophysiological functions, such as motor coordination, respiratory control, muscle tone and pain processing. The relevance of the GlyR function is further highlighted by the presence of abnormal glycinergic inhibition in many pathophysiological states, such as hyperekplexia, epilepsy, autism and chronic pain. In this context, previous studies have shown that the functional inhibition of GlyRs containing the α3 subunit is a pivotal mechanism of pain hypersensitivity. This pathway involves the activation of EP2 receptors and the subsequent PKAdependent phosphorylation of α3GlyRs within the intracellular domain (ICD), which decrease the GlyR-associated currents and enhance neuronal excitability. Despite the importance of this mechanism of glycinergic dis-inhibition associated with dysfunctional α3GlyRs, our current understanding of the molecular events involved is limited. Here, we report that the activation of PKA signaling pathway decreases the unitary conductance of α3GlyRs. We show in addition that the substitution of the PKAtargeted serine with a negatively charged residue within the ICD of α3GlyRs and of chimeric receptors combining bacterial GLic and α3GlyR was sufficient to generate receptors with reduced conductance. Thus, our findings reveal a potential biophysical mechanism of glycinergic dis-inhibition and suggest that post-translational modifications of the ICD, such as phosphorylation, may shape the conductance of other pLGICs. Glycine receptors (GlyRs) belong to the pentameric ligand-gated ion channel (pLGIC) family. GlyRs are anion-permeable channels, allowing the fast influx of chloride and the control of neuronal excitability. An individual GlyR subunit is composed by an extracellular domain (ECD), four transmembrane domains (TM1-4) and an intracellular domain between the TM3 and TM4 domains (ICD) 1-4. To date, a single β subunit and four α subunits (α1-4) has been described. The α subunits share a high degree of sequence identity (≈75%). Nevertheless, they exhibit important differences in their biophysical and pharmacological properties as well as in their distribution along the CNS 1,3,4. In the mammalian CNS, GlyR activity critically controls neurophysiological functions such as motor coordination, respiratory control, muscle tone, as well as pain processing 2,3,5-13. The importance of glycinergic inhibition was first recognized in studies using the GlyR antagonist strychnine 14,15. Later, genetic studies found that mutations in the GlyR α1 and β genes are linked to hyperekplexia in humans 16. More recent evidence has shown that specific GlyR subunits may play key roles in several diseases. For example, while the α1 subunit has been linked to tumorigenesis and alcohol intoxication 17,18 , mutations in the α2 subunit have been linked to autism 19. Alterations in the RNA processing of α3 subunits generates hyperactive receptors, which have been rela...

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The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

Cited by 14 publications

References 49 publications

Ion Channel Formation by Amyloid-β42 Oligomers but Not Amyloid-β40 in Cellular Membranes

Ion Channel Formation by Amyloid-β42 Oligomers but Not Amyloid-β40 in Cellular Membranes

Role of Plant Derived Alkaloids and Their Mechanism in Neurodegenerative Disorders

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

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