title: Sigma-1 (σ₁) receptor deficiency reduces β-amyloid(25-35)-induced hippocampal neuronal cell death and cognitive deficits through suppressing phosphorylation of the NMDA receptor NR2B.
abstract: In early Alzheimer's disease (AD) brain, reduction of sigma-1 receptors (σ1R) is detected. In this study, we employed male heterozygous σ1R knockout (σ1R(+/-)) mice showing normal cognitive performance to investigate association of σ1R deficiency with AD risk. Herein we report that a single injection (i.c.v.) of Aβ(25-35) impaired spatial memory with approximately 25% death of pyramidal cells in the hippocampal CA1 region of WT mice (Aβ(25-35)-WT mice), whereas it did not cause such impairments in σ1R(+/-) mice (Aβ(25-35)-σ1R(+/-) mice). Compared with WT mice, Aβ(25-35)-WT mice showed increased levels of NMDA-activated currents (INMDA) and NR2B phosphorylation (phospho-NR2B) in the hippocampal CA1 region at 48 h after Aβ25-35-injection (post-Aβ(25-35)) followed by approximately 40% decline at 72 h post-Aβ(25-35) of their respective control levels, which was inhibited by the σ1R antagonist NE100. In Aβ(25-35)-WT mice, the administration of NR2B inhibitor Ro25-6981 or NE100 on day 1-4 post-Aβ(25-35) attenuated the memory deficits and loss of pyramidal cells. By contrast, Aβ(25-35)-σ1R(+/-) mice showed a slight increase in the INMDA density and the phospho-NR2B at 48 h or 72 h post-Aβ25-35 compared to σ1R(+/-) mice. Treatment with σ1R agonist PRE084 in Aβ(25-35)-σ1R(+/-) mice caused the same changes in the INMDA density and the phospho-NR2B as those in Aβ(25-35)-WT mice. Furthermore, Aβ(25-35)-σ1R(+/-) mice treated with the NMDA receptor agonist NMDA or PRE084 on day 1-4 post-Aβ(25-35) showed a loss of neuronal cells and memory impairment. These results indicate that the σ1R deficiency can reduce Aβ(25-35)-induced neuronal cell death and cognitive deficits through suppressing Aβ(25-35)-enhanced NR2B phosphorylation.
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Sha
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Chen
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Conghui
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Pinghui
authors.initials: P
authors.lastname: Jie
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, 65 Tsurumai, Nagoya 466-8550, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sokabe
authors.affiliation: State Key Lab of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China; Department of Physiology, Nanjing Medical University, Nanjing 210029, China. Electronic address: lingchen@njmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017480:Receptors, sigma / Q000172:deficiency* / Q000235:genetics; D065852:Spatial Memory / Q000187:drug effects; D013997:Time Factors; D000097605:Sigma-1 Receptor
chemical_list: D016229:Amyloid beta-Peptides; D018683:Excitatory Amino Acid Agents; D016202:N-Methylaspartate; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C121001:NR2B NMDA receptor; C074636:amyloid beta-protein (25-35)
keywords: Alzheimer's disease (AD); Apoptosis; N-methyl-D-aspartate receptor (NMDAr); Sigma-1 receptor (σ(1)R); Spatial memory; β-Amyloid (Aβ)