VCAM1 Drives Vascular Inflammation Leading to Continuous Cortical Neuronal Loss Following Chronic Cerebral Hypoperfusion

Article type: Research Article

Authors: Sun, Ruihua^{a; b} | Shang, Junkui^a | Yan, Xi^a | Zhao, Jingran^{a; b} | Wang, Wan^{a; b} | Wang, Wenjing^a | Li, Wei^a | Gao, Chenhao^a | Wang, Fengyu^a | Zhang, Haohan^a | Wang, Yanliang^{a; c} | Cao, Huixia^{a; c} | Zhang, Jiewen^{a; b; *}

Affiliations: [a] Department of Neurology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, Henan, China | [b] Department of Neurology, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China | [c] Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Zhengzhou, Henan, China

Correspondence: [*] Correspondence to: Jiewen Zhang, Department of Neurology, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China 450003, China. E-mail: [email protected].

Abstract: Background:Chronic cerebral hypoperfusion (CCH) is associated with neuronal loss and blood-brain barrier (BBB) impairment in vascular dementia (VaD). However, the relationship and the molecular mechanisms between BBB dysfunction and neuronal loss remain elusive. Objective:We explored the reasons for neuron loss following CCH. Methods:Using permanent bilateral common carotid artery occlusion (2VO) rat model, we observed the pathological changes of cortical neurons and BBB in the sham group as well as rats 3d, 7d, 14d and 28d post 2VO. In order to further explore the factors influencing neuron loss following CCH with regard to cortical blood vessels, we extracted cortical brain microvessels at five time points for transcriptome sequencing. Finally, integrin receptor a4β1 (VLA-4) inhibitor was injected into the tail vein, and cortical neuron loss was detected again. Results:We found that cortical neuron loss following CCH is a continuous process, but damage to the BBB is acute and transient. Results of cortical microvessel transcriptome analysis showed that biological processes related to vascular inflammation mainly occurred in the chronic phase. Meanwhile, cell adhesion molecules, cytokine-cytokine receptor interaction were significantly changed at this phase. Among them, the adhesion molecule VCAM1 plays an important role. Using VLA-4 inhibitor to block VCAM1-VLA-4 interaction, cortical neuron damage was ameliorated at 14d post 2VO. Conclusion:Injury of the BBB may not be the main reason for persistent loss of cortical neurons following CCH. The continuous inflammatory response within blood vessels maybe an important factor in the continuous loss of cortical neurons following CCH.

Keywords: Blood-brain barrier, chronic cerebral hypoperfusion, inflammation, neuron, VCAM1

DOI: 10.3233/JAD-221059

Journal: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1541-1555, 2023