Sigma-1 (σ1) receptor deficiency reduces β-amyloid25-35-induced hippocampal neuronal cell death and cognitive deficits through suppressing phosphorylation of the NMDA receptor NR2B

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 Aβ25-35 impaired spatial memory with approximately 25% death of pyramidal cells in the hippocampal CA1 region of WT mice (Aβ25-35-WT mice), whereas it did not cause such impairments in σ1R+/- mice (Aβ25-35-σ1R+/- mice). Compared with WT mice, Aβ25-35-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-Aβ25-35) followed by approximately 40% decline at 72 h post-Aβ25-35 of their respective control levels, which was inhibited by the σ1R antagonist NE100. In Aβ25-35-WT mice, the administration of NR2B inhibitor Ro25-6981 or NE100 on day 1-4 post-Aβ25-35 attenuated the memory deficits and loss of pyramidal cells. By contrast, Aβ25-35-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 Aβ25-35-σ1R+/- mice caused the same changes in the INMDA density and the phospho-NR2B as those in Aβ25-35-WT mice. Furthermore, Aβ25-35-σ1R+/- mice treated with the NMDA receptor agonist NMDA or PRE084 on day 1-4 post-Aβ25-35 showed a loss of neuronal cells and memory impairment. These results indicate that the σ1R deficiency can reduce Aβ25-35-induced neuronal cell death and cognitive deficits through suppressing Aβ25-35-enhanced NR2B phosphorylation.