Amyloid toxicity is enhanced after pharmacological or genetic invalidation of the σ1 receptor.

Abstract

The sigma-1 receptor (S1R) is a molecular chaperone which activity modulates several intracellular signals including calcium mobilization at mitochondria-associated endoplasmic reticulum membranes. S1R agonists are potent neuroprotectants against neurodegenerative insults and particularly in rodent models of Alzheimer's disease (AD). We here analyzed whether S1R inactivation modifies vulnerability to amyloid toxicity in AD models. Two strategies were used: (1) amyloid β[25-35] (Aβ25-35) peptide (1, 3, 9nmol) was injected intracerebroventricularly in mice treated repeatedly with the S1R antagonist NE-100 or in S1RKO mice, and (2) WT, APPSweInd, S1RKO, and APPSweInd/S1RKO mice were created and female littermates analyzed at 8 months of age. Learning deficits, oxidative stress, Bax level and BDNF content in the hippocampus were analyzed. Aβ25-35 induced learning impairment, oxidative stress, Bax induction and BDNF alteration at lower dose in NE-100-treated mice or S1RKO mice as compared to WT animals. The extent of learning deficits and biochemical alterations were also higher in APPSweInd/S1RKO mice as compared to WT, APPSweInd, and S1RKO animals. S1R inactivation or altered S1R expression augmented the pathological status in pharmacologic and genetic AD mouse models. These observations, in relation with the well-known protective effects of S1R agonists, are coherent with a role of signal amplifier in neurodegeneration and neuroprotection proposed for S1R in AD and related neurodegenerative disorders.

• Authors: Tangui Maurice, Manon Strehaiano, Fanny Duhr, Nathalie Chevallier
• Journal: Behavioural brain research (Behav Brain Res) Vol. 339 Pg. 1-10 (Feb 26 2018) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 29129596 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Neuroprotective Agents
• Peptide Fragments
• Receptors, sigma
• amyloid beta-protein (25-35)

Topics

• Alzheimer Disease (genetics, metabolism)
• Amyloid beta-Peptides (metabolism, pharmacology)
• Animals
• Disease Models, Animal
• Hippocampus (drug effects, metabolism)
• Male
• Memory Disorders (chemically induced, genetics)
• Mice, Inbred C57BL
• Neuroprotective Agents (pharmacology)
• Peptide Fragments (metabolism, pharmacology)
• Receptors, sigma (drug effects, genetics, metabolism)
• Sigma-1 Receptor