Impact of Two Neuronal Sigma-1 Receptor Modulators, PRE084 and DMT, on Neurogenesis and Neuroinflammation in an Aβ1-42-Injected, Wild-Type Mouse Model of AD.

Emőke Borbély,Ildikó Schuster,Lívia Fülöp,Zsolt Bozsó,Botond Penke,Viktória Varga,Titanilla Szögi

doi:10.3390/ijms23052514

Emőke Borbély, Ildikó Schuster + Show 5 more

Open Access

https://doi.org/10.3390/ijms23052514

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Abstract

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 anti-neuroinflammatory 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.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory loss, impaired learning, and cognitive dysfunction
In those co-treated with both Aβ1-42 and DMT, hardly any Bromo-2 -Deoxyuridine (BrdU)+ stem cells were detected in the subgranular zone (SGZ) (Aβ1-42-DMT vs. PBS-PBS p ≤ 0.0001, vs. Aβ1-42-PBS p = 0.005, vs. Aβ1-42-PRE084 p ≤ 0.0001; PBS-DMT vs. PBS-PBS p = 0.001, vs. PBS-PRE084 p ≤ 0.0001)
In those treated with Aβ1-42-PBS and PBS-PRE084, the number of immature neurons was significantly higher compared to the control group (PBS-PBS vs. Aβ1-42-PBS p = 0.037, vs. PBS-PRE084 p ≤ 0.0001, vs. Aβ1-42PRE084 p ≤ 0.0001)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory loss, impaired learning, and cognitive dysfunction. The main pathological hallmarks of AD are extracellular amyloid plaques and intracellular neurofibrillary tangles accumulated in the cerebral tissue [1], which first appear in the hippocampal and entorhinal regions of the brain, explaining the impairment of cognitive functions [2]. These changes are accompanied by the damage of synaptic connections, and neuronal death. The abnormal cleavage of amyloid precursor protein (APP) by β- and γ-secretases predominantly yields 40 to 43 amino acid long amyloid-β (Aβ) peptides, which aggregate, and manifest as cerebral deposits Besides forming plaques, these oligomeric forms of Aβ are thought to be neurotoxic [3,4,5,6]. SR ligands are being recognized as promising therapeutic agents for treating or alleviating AD [6,14,15,16]

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