Alzheimer’s disease (AD) is the most common form of dementia characterized by cognitive
dysfunctions. Pharmacological interventions to slow the progression of AD are intensively studied. A
potential direction targets neuronal sigma-1 receptors (S1Rs). S1R ligands are recognized as promising
therapeutic agents that may alleviate symptom severity of AD, possibly via preventing amyloid-β-
(Aβ-) induced neurotoxicity on the endoplasmic reticulum stress-associated pathways. Furthermore,
S1Rs may also modulate adult neurogenesis, and the impairment of this process is reported to be
associated with AD. We aimed to investigate the effects of two S1R agonists, dimethyltryptamine
(DMT) and PRE084, in an Aβ-induced in vivo mouse model characterizing neurogenic and antineuroinflammatory symptoms of AD, and the modulatory effects of S1R agonists were analyzed by
immunohistochemical methods and western blotting. DMT, binding moderately to S1R but with high
affinity to 5-HT receptors, negatively influenced neurogenesis, possibly as a result of activating both
receptors differently. In contrast, the highly selective S1R agonist PRE084 stimulated hippocampal
cell proliferation and differentiation. Regarding neuroinflammation, DMT and PRE084 significantly
reduced Aβ1-42-induced astrogliosis, but neither had remarkable effects on microglial activation. In
summary, the highly selective S1R agonist PRE084 may be a promising therapeutic agent for AD.
Further studies are required to clarify the multifaceted neurogenic and anti-neuroinflammatory roles
of these agonists. CLICK TO REVIEW
Keywords: Alzheimer’s disease; Aβ1-42-induce mouse model; neurogenesis; neuroinflammation;
sigma-1 receptor; dimethyltryptamine; PRE084