Kaige Ma,1,* Chanyuan An,1,* Mai Li,1 Yuming Zhang,2 Minghe Ren,1 Yuyang Wei,3 Wenting Xu,1 Ruoxi Wang,4 Yudan Bai,1 Hanyue Zhang,1 Xiyue Liu,1 Shengfeng Ji,4 Xinlin Chen,1,5 Kun Zhu6 

1Department/Institute of Neurobiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, People’s Republic of China; 2Department of Anesthesiology, Shaanxi Provincial People’s Hospital, Xi’an, 710068, People’s Republic of China; 3School of Forensic Medicine, Southern Medical University, Guangdong, 510515, People’s Republic of China; 4Department of Optometry, Fenyang College Shanxi Medical University, Fenyang, 032200, People’s Republic of China; 5Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, 710061, People’s Republic of China; 6Department of Neurology, the First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xinlin Chen; Kun Zhu, Email chenxl@xjtu.edu.cn; kunzhu@xjtu.edu.cn

Purpose: β-amyloid overload-induced neuroinflammation and neuronal loss are key pathological changes that occur during the progression of Alzheimer’s disease (AD). Dexmedetomidine (Dex) exhibits neuroprotective and anti-inflammatory effects on the nervous system. However, the effect of Dex in AD mice remains unclear, and its neuroprotective regulatory mechanism requires further investigation. This study aimed to reveal how Dex protects against Aβ induced neuropathological changes and behavior dysfunction in AD mice.
Methods: An AD mouse model was established by the injection of Aβ into the brains of mice, followed by intraperitoneal injection with Dex. CXCL2 overexpression and Yohimbine, a Dex inhibitor, were used to investigate the role of Dex and CXCL2 in the regulation of neuronal loss, cognitive decline, and anxiety-like behavior in AD mice. Behavioral tests were performed to evaluate the cognitive and anxiety status of the mice. Nissl staining and immunofluorescence experiments were conducted to evaluate the status of the hippocampal neurons and astrocytes. qRT-PCR was performed to detect the expression of CXCL2, IL-1β, INOS, SPHK1, Bcl2, IFN-γ, and Caspase 1. The malondialdehyde (MDA) level was detected using an ELISA kit. Terminal TUNEL and Fluoro-Jade C (FJC) staining were used to measure the cell apoptosis rate.
Results: In AD mice, cognitive decline and anxiety-like behaviors were significantly improved by the Dex treatment. The number of neurons was increased in mice in the Dex + AD group compared to those in the AD group, and the number of astrocytes was not significantly different between the two groups. CXCL2, IL-1β, iNOS, and SPHK1 levels were significantly lower in Dex-treated AD mice than those in AD mice. Overloading of CXCL2 or Yohimbine reversed the protective effect of Dex on neuron number and cognitive and anxiety symptoms in AD mice.
Conclusion: Our results suggest that Dex exerts neuroprotective effects by downregulating CXCL2. Dex shows potential as a therapeutic drug for AD.

Keywords: dexamethasone, Alzheimer’s disease, chemokine CXCL2, anxiety, cognitive dysfunction, behavioral Tests