The emerging role of the sigma-1 receptor in autophagy: hand-in-hand targets for the treatment of Alzheimer’s

ABSTRACT

Introduction

Autophagy is a cellular catabolic mechanism that helps clear damaged cellular components and is essential for normal cellular and tissue function. The sigma-1 receptor (σ-1R) is a chaperone protein involved in signal transduction, neurite outgrowth, and plasticity, improving memory, and neuroprotection. Recent evidence shows that σ-1R can promote autophagy. Autophagy activation by the σ-1Rs along with other neuroprotective effects makes it an interesting target for the treatment of Alzheimer’s disease. AF710B, T-817 MA, and ANAVEX2-73 are some of the σ-1R agonists which have shown promising results and have entered clinical trials. These molecules have also been found to induce autophagy and show cytoprotective effects in cellular models.

Areas covered

This review provides insight into the current understanding of σ-1R functions related to autophagy and their role in alleviating AD.

Expert Opinion

We propose a mechanism through which the activation of σ-1R and autophagy could alter amyloid precursor protein processing to inhibit amyloid-β production by reconstituting cholesterol and gangliosides in the lipid raft to offer neuroprotection against AD. Future AD treatment could involve the combined targeting of the σ-1R and autophagy activation. We suggest that future studies investigate the link between autophagy the σ-1R and AD.

KEYWORDS:

• Alzheimer’s disease
• autophagy
• non-opioid-sigma-1 receptor
• mitochondrial stress
• neurodegenerative disease
• sigma-1 agonists
• lipid raft
• sigma-1 receptor
• avp-786
• anavex2-73

Article highlights

• The σ-1R’s expression increases with age; however, in Alzheimer’s disease (AD) pathology, it decreases.

• The decrease in σ-1R expression during AD coincides with an age-related decrease in autophagy.

• The σ-1R may compensate for loss of receptors and autophagic machinery during healthy aging.

• Activation of the σ-1R can induce cytoprotective autophagic pathways.

• Promising σ-1R ligands used as AD drugs have been shown to induce autophagy.

• Autophagy plays a key role in the progression of AD pathology This box summarizes key points contained in the article.

Author contributions

J.M.B and T.T conceived the idea for the manuscript, MIP, DSM, and JMB drafted the manuscript. J.M.B and T.T edited the final draft.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

J.M. Brimson and M.I. Prasanth were funded by the Rachadapisek Sompote Fund for Postdoctoral Fellowship, Chulalongkorn University. D.S. Malar was funded by The Second Century Fund (C2F) for Postdoctoral Fellowship, Chulalongkorn University.