ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1587219
This article is part of the Research TopicMolecular mechanisms of neurodegenerationView all 14 articles
A new pathway for neuroprotection against Tau hyperphosphorylation via δ-Opioid receptor initiated inhibition of CDK5 and AMPK signaling
Provisionally accepted
- 1Fudan University, Shanghai, Shanghai Municipality, China
- 2First People's Hospital of Changzhou, Changzhou, Jiangsu Province, China
- 3University of Cagliari, Cagliari, Sardinia, Italy
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Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by decreased memory and cognitive impairment. Abnormal tau hyperphosphorylation ultimately forms neurofibrillary tangles, which is one of the most important pathological features of AD. Since we have previously shown that the δ-opioid receptor (DOR) is neuroprotective in the brain, we asked if DOR plays any role in the control of tauopathy. In the PC12 cell model with okadaic acid-induced tau hyperphosphorylation, cell viability and cytotoxicity were evaluated by using CCK8 assay kit and lactate dehydrogenase cytotoxicity assay kit. The techniques of western blot and immunofluorescence were used to investigate the effect of DOR on tau hyperphosphorylation. We found that DOR activation inhibited okadaic acid-induced tau hyperphosphorylation in PC12 cells and attenuated the cell cycle reactivation and apoptosis. The DOR effect was blocked by Naltrindole, a DOR antagonist. Furthermore, the mechanistic studies showed that the DOR displayed its effect by reducing the expression of cyclin-dependent kinase (CDK) 5 and AMP-activated protein kinase (AMPK) in the model of tauopathy. Our novel findings suggest that DOR signaling may protect neurons from AD injury by inhibiting tau hyperphosphorylation.
Keywords: Alzheimer's disease, AMPK, CDK5, δ-opioid receptor, Neuroprotection, tau hyperphosphorylation
Received: 04 Mar 2025; Accepted: 03 Jun 2025.
Copyright: © 2025 Li, Xu, Balboni and Xia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ying Xia, Fudan University, Shanghai, 200433, Shanghai Municipality, China
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