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] (Aβ_25-35) peptide (1, 3, 9nmol) was injected intracerebroventricularly in mice treated repeatedly with the S1R antagonist NE-100 or in S1RKO mice, and (2) WT, APP_SweInd, S1RKO, and APP_SweInd/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. Aβ_25-35 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 APP_SweInd/S1RKO mice as compared to WT, APP_SweInd, 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.

Keywords: Alzheimer's disease; Amyloid toxicity; Knockout mice; Learning and memory; Sigma-1 receptor.