Activation of the sigma-1 receptor attenuates blood–brain barrier disruption by inhibiting amyloid deposition in Alzheimer's disease mice. (23rd March 2022)

• Record Type: Journal Article
• Authors: An, Yang; Qi, Yue; Li, Ying; Li, Zhao; Yang, Caiyu; Jia, Dong
• Is Part Of: Neuroscience letters. Volume 774(2022)
• Publication Date: 2022-03-23
• Subjects: Sig-1R sigma-1 receptor -- AD Alzheimer's disease -- BBB blood–brain barrier -- Aβ amyloid beta -- ICV intracerebroventricular -- ZO-1 zonula occludens-1 -- LRP-1 low-density lipoprotein receptor-related protein 1 -- PBS phosphate-buffered saline -- VEGF vascular endothelial growth factor; Alzheimer's disease -- sig-1R -- Blood–brain barrier -- VEGF -- LRP-1; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2022.136528
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Sig-1R agonist PRE084 treatment attenuated learning and memory deficits in AD mice. PRE084 lowed the soluble and insoluble Aβ1-40 and Aβ1-42 levels in the brain. PRE084 ameliorated BBB leakage and structural damage. PRE084 increased LRP1 and VEGF expressions. Abstract: The sigma-1 receptor is an important target for drug development in several neuropsychiatric diseases, including Alzheimer's disease (AD). Accumulating evidence has shown that the integrity and functional activity of the blood–brain barrier (BBB) in AD are impaired, which is closely related to the movement of amyloid beta (Aβ) across the BBB and the formation of Aβ plaques. In this study, we investigated the effects of sigma-1 receptor activation on BBB disruption and Aβ levels in AD mice. We found that PRE-084, a sigma-1 receptor agonist, attenuated learning and memory deficits in Aβ–injected mice, significantly increased levels of low-density lipoprotein receptor-related protein 1 (LRP-1), and lowered the Aβ level synergistically in the brain. Moreover, the upregulation of vascular endothelial growth factor (VEGF) levels through the sigma-1 receptor may be involved in the reduction of the BBB permeability by PRE-084. The identification of this previously unexplored role of the sigma-1 receptor in alleviating BBB disruption via upregulating the levels of VEGF and LRP-1 in AD suggests that reversing BBB dysfunction through sigma-1 receptor activation may be a promising treatment for AD.