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. 2022 Aug:202:115149.
doi: 10.1016/j.bcp.2022.115149. Epub 2022 Jun 14.

Z-Guggulsterone attenuates cognitive defects and decreases neuroinflammation in APPswe/PS1dE9 mice through inhibiting the TLR4 signaling pathway

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Z-Guggulsterone attenuates cognitive defects and decreases neuroinflammation in APPswe/PS1dE9 mice through inhibiting the TLR4 signaling pathway

Jing Liu et al. Biochem Pharmacol. 2022 Aug.

Abstract

Growing evidence indicates that inflammatory damage is implicated in the pathogenesis of Alzheimer's disease (AD). Z-Guggulsterone (Z-GS) is a natural steroid, which is extracted from Commiphora mukul and has anti-inflammatory effects in vivo and in vitro. In the present study, we investigated the disease-modifying effects of chronic Z-GS administration on the cognitive and neuropathological impairments in the transgenic mouse models of AD. We found that chronic Z-GS administration prevented learning and memory deficits in the APPswe/PS1dE9 mice. In addition, Z-GS treatment significantly decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that Z-GS treatment markedly alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated TLR4/NF-κB signaling pathways in APPswe/PS1dE9 mice were remarkably inhibited by Z-GS treatment, which was achieved via suppressing the phosphorylation of JNK. Collectively, our data demonstrate that chronic Z-GS treatment restores cognitive defects and reverses multiple neuropathological impairments in the APPswe/PS1dE9 mice. This study provides novel insights into the neuroprotective effects and neurobiological mechanisms of Z-GS on AD, indicating that Z-GS is a promising disease-modifying agent for the treatment of AD.

Keywords: Alzheimer’s disease; Amyloid-β peptide; Inflammation; TLR4; Z-Guggulsterone.

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