The Role of Sigma-1 Receptors in an Alzheimer's Disease Mouse Model

Abstract

Alzheimer's disease (AD) is an incurable disease characterized by a slow, progressive decline in cognitive functions as well as the presence of amyloid-beta (Aβ) plaques and neurofibrillary tangles. Interestingly, two thirds of AD patients are women who have a faster disease progression. Despite this clinical profile, sex differences in AD pathophysiology are largely ignored at the basic and clinical levels. Current therapies provide only mild to moderate improvement in patient symptoms. There is, therefore, an urgent need to expand our understanding of the underlying pathophysiology of AD, and to obtain alternative hypotheses and therapeutics. A recent and promising development involves the sigma-1 receptor (Sig1R), a protein regulated by steroid hormones, which has been implicated in AD. Most interestingly, Sig1R agonists have been shown to ameliorate cognitive deficits in an AD mouse model. Here, we investigated the role of Sig1Rs in an Aβ25-35-infusion mouse model of AD, using behavioural paradigms. Previous studies employing this model have demonstrated Aβ-induced impairments in learning and memory in young male rodents, while no work has been done on females. We examined cognitive function following Aβ25-35 infusion in wild-type and knock-out Sig1R adult male and female mice using the Morris water maze, spontaneous alternation in the Y-maze, and forced alternation in the Y-maze tasks. Overall, the data unexpectedly shows that genotype, Aβ25-35-treatment, and sex had no effect on cognitive functions. These results suggest that additional efforts are required to obtain a working Aβ25-35-infusion model in our Sig1R mice and behavioural tasks. Future experiments will hopefully shed some light on the link between Sig1Rs and AD, which could lead to the development of therapeutics and disease prevention.