Sex-Specific Role of Sigma-1 Receptor in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly and affects a growing number of people every year, which are mostly women. Despite years of research, there is no cure and no treatment effectively alter disease progression. A failure to examine sex differences in AD research may be partially to blame. Thus, novel therapeutic interventions are greatly needed that account for potential sex differences in disease pathophysiology. One promising target for prevention and treatment of AD is the sigma 1 receptor (Sig1R), a protein regulated by sex hormones, synapse function, and cognition. Activation and overexpression of Sig1R is known to be anti-amnesic and neuroprotective, whereas loss or dysfunction in Sig1R is associated with neurodegeneration. Interestingly, brains from early AD patients exhibit a lower density of Sig1R and Sig1R are decreased in post-mortem AD hippocampus. Therefore, Sig1R reduction could lead to a hostile environment and contribute to AD progression. Here, we used two mouse model of AD, Aβ25-35 infusion model and 3xTg-AD model, to investigate how Sig1R sex-specifically modulates AD pathology. We first looked at how Sig1R protein levels are altered by sex and AD pathology. We found that the triple transgenic mutation significantly alters Sig1R expression. Next, we examined how synapses are modified by sex and AD pathology and if changes can be rescued by Sig1R activation. Interestingly, we found differences in synaptic plasticity between the sexes. Furthermore, we observed that male and female mice respond differently to Sig1R activation. Our results also revealed a sex-specific baseline difference in surface GluA2 levels. Given that synapse loss is a morphological reflection of synaptic dysfunction, we finally studied the structural integrity of the hippocampus. We found that Aβ25-35 infusion and triple transgenic mutation reduce hippocampal volumetry, with no apparent sex differences. Taken together, our findings support the idea that synaptic dysfunction is different between males and females.