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AdipoRon promotes amyloid-ß clearance through enhancing autophagy via nuclear GAPDH-induced sirtuin 1 activation in Alzheimer's disease.
Sun, Fengjiao; Wang, Jiangong; Meng, Lingbin; Zhou, Zhenyu; Xu, Yong; Yang, Meizi; Li, Yixin; Jiang, Tianrui; Liu, Bin; Yan, Haijing.
Afiliación
  • Sun F; Medical Research Center, Binzhou Medical University Hospital, Binzhou, China.
  • Wang J; Department of Pharmacology, School of Basic Medicine, Binzhou Medical University, Yantai, China.
  • Meng L; Medical Research Center, Binzhou Medical University Hospital, Binzhou, China.
  • Zhou Z; Department of Pharmacology, School of Basic Medicine, Binzhou Medical University, Yantai, China.
  • Xu Y; Department of Pharmacology, School of Basic Medicine, Binzhou Medical University, Yantai, China.
  • Yang M; Department of Pharmacology, School of Basic Medicine, Binzhou Medical University, Yantai, China.
  • Li Y; Department of Pharmacology, School of Basic Medicine, Binzhou Medical University, Yantai, China.
  • Jiang T; Department of Pharmacology, School of Basic Medicine, Binzhou Medical University, Yantai, China.
  • Liu B; Department of Pharmacology, School of Basic Medicine, Binzhou Medical University, Yantai, China.
  • Yan H; Department of Pharmacology, School of Basic Medicine, Binzhou Medical University, Yantai, China.
Br J Pharmacol ; 181(17): 3039-3063, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38679474
ABSTRACT
BACKGROUND AND

PURPOSE:

Amyloid-ß (Aß) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development of AD impairs autophagy, which results in an imbalanced clearance of Aß. Our previous research demonstrated that AdipoRon, an agonist of adiponectin receptors, decreased the deposition of Aß and enhanced cognitive function in AD. However, the exact mechanisms by which AdipoRon affects Aß clearance remain unclear. EXPERIMENTAL

APPROACH:

We studied how AdipoRon affects autophagy in HT22 cells and APP/PS1 transgenic mice. We also investigated the signalling pathway involved and used pharmacological inhibitors to examine the role of autophagy in this process. KEY

RESULTS:

AdipoRon promotes Aß clearance by activating neuronal autophagy in the APP/PS1 transgenic mice. Interestingly, we found that AdipoRon induces the nuclear translocation of GAPDH, where it interacts with the SIRT1/DBC1 complex. This interaction then leads to the release of DBC1 and the activation of SIRT1, which in turn activates autophagy. Importantly, we found that inhibiting either GAPDH or SIRT1 to suppress the activity of SIRT1 counteracts the elevated autophagy and decreased Aß deposition caused by AdipoRon. This suggests that SIRT1 plays a critical role in the effect of AdipoRon on autophagic induction in AD. CONCLUSION AND IMPLICATIONS AdipoRon promotes the clearance of Aß by enhancing autophagy through the AdipoR1/AMPK-dependent nuclear translocation of GAPDH and subsequent activation of SIRT1. This novel molecular pathway sheds light on the modulation of autophagy in AD and may lead to the development of new therapeutic strategies targeting this pathway.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Ratones Transgénicos / Péptidos beta-Amiloides / Sirtuina 1 / Enfermedad de Alzheimer Límite: Animals / Humans / Male Idioma: En Revista: Br J Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autofagia / Ratones Transgénicos / Péptidos beta-Amiloides / Sirtuina 1 / Enfermedad de Alzheimer Límite: Animals / Humans / Male Idioma: En Revista: Br J Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido