Antroquinonol mitigates Tau hyperphosphorylation, neuronal damage and cognitive impairments in a chronic cerebral ischemia rat model

Ling-Yu Yang; Chiu-Hao Hsu; Ya-Wen Cheng; Kuo-Wei Chen; Sheng-Che Chou; Yong-Ren Chen; Yi-Tzu Chen; Chuan-Rou Deng; I-Chin Chen; Meng-Fai Kuo; Kuo-Chuan Wang

doi:10.1016/j.biopha.2025.118271

Antroquinonol mitigates Tau hyperphosphorylation, neuronal damage and cognitive impairments in a chronic cerebral ischemia rat model

Biomed Pharmacother. 2025 Jun 21:189:118271. doi: 10.1016/j.biopha.2025.118271. Online ahead of print.

Authors

Affiliations

¹ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
² Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
³ Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
⁴ Non-Invasive Cancer Therapy Research Institute, Taipei, Taiwan; Adjunct Visiting Staff, Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
⁵ Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: wangkclab@gmail.com.

PMID: 40544750
DOI: 10.1016/j.biopha.2025.118271

Abstract

Chronic cerebral ischemia (CCI) induced hyperphosphorylated Tau has been associated with an increased risk of neurodegenerative disorders such as Alzheimer's and vascular dementia. This study investigated the neuroprotective effects of Antroquinonol (AQ), an ubiquinone derivative from Antrodia camphorata with anti-inflammatory and antioxidant properties. Bilateral internal carotid artery ligation (BICAL) in male Wistar rats and mixed rat primary neuron/glia co-cultures exposed to a hypoxia and hypoglycemia (HH) environment were used as experimental CCI models to investigate the therapeutic effects and mechanisms of AQ. AQ was administered daily at low or high doses for 28 days after BICAL induction. Two and four weeks after BICAL surgery, the functional and cognitive outcomes were evaluated by rotarod test, open field test (OFT), novel object recognition (NOR) and Y-maze test. Nissl, TUNEL, IHC and ICC staining, and Western blot analysis were used to evaluate the effects and underlying mechanisms of AQ in the treatment of CCI. The results showed that both low and high doses of AQ treatment significantly ameliorated motor deficits, anxiety-like behavior, and cognitive impairments in BICAL rats at 2 or 4 weeks post-CCI. Histological and molecular analyses revealed that AQ reduced neuronal injury, microglia activation, apoptosis, and Tau hyperphosphorylation in the cortex and hippocampus regions. We also found that AQ inhibited HH-induced hyperphosphorylation of Tau by modulating protein kinases (p-GSK3β Y216 and p-mTOR), LC3II, and p-NRF2 proteins in cultured cells, suggesting roles in kinase regulation, autophagy, and antioxidation. These findings support AQ as a promise therapeutic candidate for treating CCI-related neurodegenerative disorders.

Keywords: Antroquinonol; Chronic cerebral ischemia (CCI); Motor and cognitive deficits; Neuroinflammation; Neuronal damage; Tau hyperphosphorylation.