Luteolin alleviates cognitive impairment in Alzheimer’s disease mouse model via inhibiting endoplasmic reticulum stress- dependent neuroinflammation

Jie-jian Kou1, Jun-zhuo Shi1, Yang-yang He1, Jiao-jiao Hao1, Hai-yu Zhang1, Dong-mei Luo1, Jun-ke Song2,3, Yi Yan4,5, Xin-mei Xie1, Guan-hua Du2,3, Xiao-bin Pang1
1 School of Pharmacy, Henan University, Kaifeng 475004, China
2 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
3 Beijing Key Laboratory of Drug Target Identification and Drug Screening, National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
4 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich 80336, Germany
5 DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich 80336, Germany
Correspondence to: Xin-mei Xie:, Guan-hua Du:, Xiao-bin Pang:,
DOI: 10.1038/s41401-021-00702-8
Received: 3 December 2020
Accepted: 17 May 2021
Advance online: 15 July 2021


Luteolin is a flavonoid in a variety of fruits, vegetables, and herbs, which has shown anti-inflammatory, antioxidant, and anti-cancer neuroprotective activities. In this study, we investigated the potential beneficial effects of luteolin on memory deficits and neuroinflammation in a triple-transgenic mouse model of Alzheimer’s disease (AD) (3 × Tg-AD). The mice were treated with luteolin (20, 40 mg · kg−1 · d−1, ip) for 3 weeks. We showed that luteolin treatment dose-dependently improved spatial learning, ameliorated memory deficits in 3 × Tg-AD mice, accompanied by inhibiting astrocyte overactivation (GFAP) and neuroinflammation (TNF-α, IL- 1β, IL-6, NO, COX-2, and iNOS protein), and decreasing the expression of endoplasmic reticulum (ER) stress markers GRP78 and IRE1α in brain tissues. In rat C6 glioma cells, treatment with luteolin (1, 10 μM) dose-dependently inhibited LPS-induced cell proliferation, excessive release of inflammatory cytokines, and increase of ER stress marker GRP78. In conclusion, luteolin is an effective agent in the treatment of learning and memory deficits in 3 × Tg-AD mice, which may be attributable to the inhibition of ER stress in astrocytes and subsequent neuroinflammation. These results provide the experimental basis for further research and development of luteolin as a therapeutic agent for AD.
Keywords: Alzheimer’s disease; luteolin; neuroinflammation; endoplasmic reticulum stress; astrocyte; 3 × Tg-AD mice; C6 cells

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