Involvement of the Sigma-1 Receptor in Neuronal Cell Death and Alzheimer's Disease

Abstract

Dysfunction in the Sigma-1 receptor (Sig-1R) is implicated in many neurodegenerative diseases such as Alzheimer’s Disease (AD). Recently, agonists of the Sig-1R have been found to be neuroprotective in AD and provide significant improvements in symptoms. The hallmarks of AD are aggregation of amyloid-β (Aβ) plaques and development of neurofibrillary tau tangles in the brain, which are thought to be correlated with progressive neuronal cell death in AD. Aβ leads to increased endoplasmic reticulum (ER) stress, decreased autophagy, and increased apoptosis, all of which may be contributing to the neuronal cell death that is seen in AD. The Sig-1R is known to reduce ER stress, increase autophagy, and decrease apoptosis. However, as of yet there is little research on the ability of the Sig-1R to specifically reduce Aβ toxicity through these pathways. Therefore, through the use of in vitro and ex vivo models, this study examined the pathways through which activation of the Sig-1R may exert its protective effects against Aβ toxicity. Here, it is shown that activation of the Sig-1R reduces neuronal cell apoptosis in vitro, and reduces tissue death in the CA3 region of the hippocampus ex vivo. Furthermore, this reduction in cell and tissue death may be a result of reduction of ER stress and a return towards baseline levels of autophagy. Together, this research provides insight as to how the Sig-1R may be an important therapeutic target in AD through protection against apoptosis and tissue death.