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

Expert Opin Ther Targets. 2021 May;25(5):401-414. doi: 10.1080/14728222.2021.1939681. Epub 2021 Jun 17.


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; anavex2-73; autophagy; avp-786; lipid raft; mitochondrial stress; neurodegenerative disease; non-opioid-sigma-1 receptor; sigma-1 agonists; sigma-1 receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / physiopathology
  • Animals
  • Autophagy / drug effects
  • Furans / pharmacology
  • Humans
  • Maleates / pharmacology
  • Molecular Targeted Therapy*
  • Receptors, sigma / agonists*
  • Receptors, sigma / metabolism
  • Spiro Compounds / pharmacology
  • Thiazolidines / pharmacology
  • Thiophenes / pharmacology


  • 1-(3-(2-(1-benzothiophen-5-yl) ethoxy) propyl)-3-azetidinol maleate
  • AF710 compound
  • Furans
  • Maleates
  • Receptors, sigma
  • Spiro Compounds
  • Thiazolidines
  • Thiophenes
  • sigma-1 receptor
  • tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride