Increased Permeability of the Blood-Brain Barrier and Alzheimer's Disease-Like Alterations in Slit-2 Transgenic Mice

Article type: Research Article

Authors: Li, Jiang-chao^{a; 1} | Han, Lu^{a; 1} | Wen, Yin-xin^a | Yang, Yong-xia^b | Li, Shuai^a | Li, Xue-song^c | Zhao, Chang-jiang^c | Wang, Ting-yu^d | Chen, Hui^a | Liu, Ying^a | Qi, Cui-ling^a | He, Xiao-dong^a | Gu, Qu-liang^b | Ye, Yu-xiang^a | Zhang, Yu^e | Huang, Ren^e | Wu, Yu-e^e | He, Rong-rong^f | Kurihara, Hiroshi^f | Song, Xiao-yu^g | Cao, Liu^{g; *} | Wang, Li-jing^{a; *}

Affiliations: [a] Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China | [b] School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China | [c] The Third People's Hospital of Foshan, Foshan, China | [d] Dongguan Xinyong Hospital, Dongguan, China | [e] Guangdong Key Laboratory of Laboratory Animals/Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong, China | [f] Anti-Stress and Health Research Center, Pharmacy College, Jinan University, Guagnzhou, China | [g] Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China

Correspondence: [*] Correspondence to: Li-jing Wang, Professor, Vascular Biology Research Institute, Guangdong Pharmaceutical University, No. 280 E Road, Higher Education Mega, Guangzhou 510006, China. Tel.: +86 20 39352126; E-mail: [email protected]; Liu Cao, Professor, Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Alzheimer's disease (AD) is a progressive neurological disorder that primarily affects memory, and its prevalence is rising. Increasing evidence suggests that dysfunction of the blood-brain barrier (BBB) may be involved in AD and other neurodegenerative diseases. Herein, we report that the permeability of the BBB is increased and that AD-like alterations are present in Slit-2 overexpressing transgenic mice. We found that behavioral change and the corresponding molecular diagnostic markers of AD, such as hippocampal neuron apoptosis, amyloid-β (Aβ) protein deposition, and acetylcholinesterase expression, were increased in the Slit-2 transgenic mice. Moreover, the endothelial cells were dysfunctional, the size of the lateral ventricle cavity increased, and the permeability of the BBB increased. Additionally, there was an increased serum level of glutamate indicating that the BBB is related to AD. Finally, histopathological analysis of other organs in the Slit-2 overexpressing mice did not show any marked abnormalities. These findings demonstrate that Slit2 overexpression may be responsible for AD-like alterations and the increased BBB permeability in these mice. Our study provides a potential novel mechanism for the development of AD.

Keywords: Alzheimer's disease, blood-brain barrier, Slit homolog 2 protein, transgenic mice

DOI: 10.3233/JAD-141215

Journal: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 535-548, 2015