The sigma-2 receptor is expressed in brain and retinal cells where it regulates key pathways involved in age-related diseases such as Alzheimers disease and synucleinopathies such as Parkinsons disease and dementia with Lewy bodies, as well as dry age-related macular degeneration (dry AMD). The normal activity of processes regulated by sigma-2, such as protein trafficking and autophagy, is impaired by cellular stresses such as oxidative stress and the build-up of amyloid-β and α-synuclein oligomers. Studies support that sigma-2 modulators can rescue biological processes that are impaired in neurodegenerative diseases.
In vitro studies of experimental sigma-2 receptor modulators demonstrated an ability to prevent the binding of amyloid-β oligomers to neurons and also to displace bound amyloid-β oligomers from neuronal receptors. In addition, transgenic mice treated sigma-2 receptor modulators performed significantly better in the Morris water maze task than did vehicle-treated mice. Taken together, these studies suggest that sigma-2 receptor modulation may be a viable approach for treating certain neurodegenerative diseases of the CNS and retina.