title: 1MeTIQ provides protection against Aβ-induced reduction of surface expression of synaptic proteins and inhibits H₂O₂-induced oxidative stress in primary hippocampal neurons.
abstract: Alzheimer's disease (AD) is associated with increased brain levels of β-amyloid (Aβ) peptides, which readily self-aggregate into fibrils and oligomers that have particularly deleterious properties toward synapses of excitatory glutamatergic neurons. Here, we examined the neuroprotective effects of 1-methyl-1,2,3,4,-tetrahydroisoquinoline (1MeTIQ) against Aβ-induced loss of synaptic proteins in cultured primary hippocampal neurons. Exposure of mature primary hippocampal neurons to 10 μM synthetic Aβ1-40 over 72 h resulted in ~60 % reduction in the surface expression of NR1 subunit of the NMDA receptor (NMDAR), PSD-95, and synaptophysin, without causing neuronal death. Concomitant treatment with 500 μM of 1MeTIQ, a low-affinity NMDAR antagonist significantly ameliorated the loss of synaptic protein markers. The neuroprotective properties of 1MeTIQ were compared with those of MK-801, which at 0.5 μM concentration also prevented Aβ1-40-induced loss of synaptic proteins in primary neuronal cultures. Furthermore, we provide novel evidence demonstrating effectiveness of 1MeTIQ in reducing the level of reactive oxygen species (ROS) in primary neuronal culture system. As oxidative stress contributes importantly to neurodegeneration in AD, 1MeTIQ may provide a dual neuroproctective effect in AD both as a NMDARs antagonist and ROS formation inhibitor. 1MeTIQ occurs endogenously at low concentrations in the brain and its synthetic form readily penetrates the blood-brain barrier after the systemic administration. Our results highlight a possibility of the application of 1MeTIQ as a neuroprotective agent in AD-related neurodegeneration.
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Kuszczyk
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Sadowski
authors.forename: Lucyna
authors.initials: L
authors.lastname: Antkiewicz-Michaluk
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Lazarewicz
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D008565:Membrane Proteins; C409466:NR1 NMDA receptor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D016708:Synaptophysin; C569015:Syp protein, mouse; D044005:Tetrahydroisoquinolines; C078592:amyloid beta-protein (1-40); C050386:1-methyl-1,2,3,4-tetrahydroisoquinoline; D016291:Dizocilpine Maleate; D006861:Hydrogen Peroxide; D051528:Guanylate Kinases