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The bexarotene derivative OAB-14 ameliorates cognitive decline in APP/PS1 transgenic mice by suppressing
Feng Zhang1, Ruo-Lin Cao2, Peng Liu3
1Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, Liaoning, PR China; Institute of Pharmacology, Shandong first Medical University, Jinan 250117, Shandong, PR China.
Abstract:
Neuroinflammation is believed to be a critical process involved in the pathophysiology of Alzheimer's disease (AD). In this study, we investigated the pharmacological ability of OAB-14, a small molecule compound derived from bexarotene, to reduce neuroinflammation and improve cognitive decline in an AD mouse model (in vivo) and its ability to regulate signaling pathways implicated in neuroinflammation in vitro. It was found that OAB-14 significantly improved the cognitive function of 11-month-old AD mice (APP/PS1 transgenic mice) in a dose-dependent manner. Simultaneously, OAB-14 dramatically inhibited the activation of microglia in the cerebral cortex and hippocampus of AD mice and dose-dependently downregulated the expression of nuclear factor kappa B (NF-κB) and NOD-like receptor protein 3 (NLRP3) in the cerebral cortex. At the cellular level, OAB-14 reversed the downregulation of M2 phenotypic markers, including mannose receptor C-type 1 (MRC1) and arginase 1 (ARG1), in lipopolysaccharide (LPS)- or amyloid-β protein oligomer (oAβ1-42)-activated BV2 microglial cells and partially restored their ability to clear Aβ. However, these effects were suppressed when peroxisome proliferator-activated receptor-γ (PPAR-γ) was specifically inhibited by GW9662, a selective PPAR-γ antagonist. These results suggested that OAB-14 could regulate microglial polarization by regulating PPAR-γ signaling, thereby mitigating neuroinflammation and improving cognitive function in AD mice.
Insights
OAB-14, a novel compound, effectively reduced neuroinflammation and improved cognitive function in Alzheimer
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Neuroinflammation is a key factor in Alzheimer's disease (AD) pathogenesis.
- Microglial activation and associated inflammatory pathways contribute to AD progression.
- Targeting neuroinflammation offers a potential therapeutic strategy for AD.
Purpose of the Study:
- To evaluate the efficacy of OAB-14, a bexarotene derivative, in mitigating neuroinflammation and cognitive decline in an Alzheimer's disease mouse model.
- To investigate the in vitro mechanisms by which OAB-14 modulates signaling pathways involved in neuroinflammation.
Main Methods:
- In vivo studies using 11-month-old APP/PS1 transgenic Alzheimer's disease mice.
- Assessment of cognitive function using behavioral tests.
- In vitro studies using BV2 microglial cells stimulated with lipopolysaccharide (LPS) or amyloid-beta oligomers (oAβ1-42).
- Analysis of microglial activation markers, inflammatory pathway expression (NF-κB, NLRP3), and M2 phenotypic markers (MRC1, ARG1).
- Pharmacological inhibition of peroxisome proliferator-activated receptor-gamma (PPAR-γ) using GW9662.
Main Results:
- OAB-14 significantly improved cognitive function in AD mice in a dose-dependent manner.
- OAB-14 inhibited microglial activation in the cerebral cortex and hippocampus of AD mice.
- OAB-14 downregulated NF-κB and NLRP3 expression and reversed M2 marker downregulation in activated microglia.
- OAB-14 partially restored microglial Aβ clearance capacity.
- The therapeutic effects of OAB-14 were dependent on PPAR-γ signaling.
Conclusions:
- OAB-14 demonstrates significant potential in ameliorating Alzheimer's disease pathology.
- OAB-14 exerts its neuroprotective effects by modulating microglial polarization via PPAR-γ signaling.
- OAB-14 represents a promising therapeutic candidate for Alzheimer's disease treatment by targeting neuroinflammation.
