The Sigma Receptors in Alzheimer’s Disease: New Potential Targets for Diagnosis and Therapy

Abstract

Sigma (σ) receptors are a class of unique proteins with two subtypes: the sigma-1 (σ1) receptor which is situated at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM), and the sigma-2 (σ2) receptor, located in the ER-resident membrane. Increasing evidence indicates the involvement of both σ1 and σ2 receptors in the pathogenesis of Alzheimer’s disease (AD), and thus these receptors represent two potentially effective biomarkers for emerging AD therapies. The availability of optimal radioligands for positron emission tomography (PET) neuroimaging of the σ1 and σ2 receptors in humans will provide tools to monitor AD progression and treatment outcomes. In this review, we first summarize the significance of both receptors in the pathophysiology of AD and highlight AD therapeutic strategies related to the σ1 and σ2 receptors. We then survey the potential PET radioligands, with an emphasis on the requirements of optimal radioligands for imaging the σ1 or σ2 receptors in humans. Finally, we discuss current challenges in the development of PET radioligands for the σ1 or σ2 receptors, and the opportunities for neuroimaging to elucidate the σ1 and σ2 receptors as novel biomarkers for early AD diagnosis, and for monitoring of disease progression and AD drug efficacy.