Mfsd2a Reverses Spatial Learning and Memory Impairment Caused by Chronic Cerebral Hypoperfusion via Protection of the Blood-Brain Barrier.

Changhua Qu,Jun Shen,Yaqing Li,Chujie Qu,Tian Li,Hao Song,Junjian Zhang,Linling Xu

doi:10.3389/fnins.2020.00461

Abstract

Disruption of the blood–brain barrier (BBB) can lead to cognitive impairment. Major facilitator superfamily domain-containing protein 2a (Mfsd2a) is a newly discovered protein that is essential for maintaining BBB integrity. However, the role of Mfsd2a in vascular cognitive impairment has not been explored yet. In this study, a rat model of chronic cerebral hypoperfusion (CCH) was established by producing permanent bilateral common carotid artery occlusion (2VO) in rats. We found that after the 2VO procedure, the rats exhibited cognitive impairment, showed increased BBB leakage within the hippocampus, and had reduced expression of the Mfsd2a protein. The overexpression of Mfsd2a in the rat hippocampus reversed these changes. Further investigations using transmission electron microscopy revealed a significantly increased rate of vesicular transcytosis in the BBB of the hippocampus of the CCH rats; the rate reduced after overexpression of Mfsd2a. Moreover, Mfsd2a overexpression did not cause changes in the expression of tight junction-associated proteins and in the ultrastructures of the tight junctions. In conclusion, Mfsd2a attenuated BBB damage and ameliorated cognitive impairment in CCH rats, and its protective effect on the BBB was achieved via inhibition of vesicular transcytosis.

Highlights

Vascular cognitive impairment (VCI) and Alzheimer’s disease are major medical issues that affect the health of the elderly population (Yang Y. et al, 2017)
These results suggest that the expression of Major facilitator superfamily domain-containing protein 2a (Mfsd2a) protein in the hippocampal CA1 region was downregulated after chronic cerebral hypoperfusion (CCH)
We have identified that the expression level of Mfsd2a protein is reduced in the hippocampus of CCH rats, leading to enhanced vesicle transcytosis and resulting in high permeability of blood–brain barrier (BBB)

Summary

Introduction

Vascular cognitive impairment (VCI) and Alzheimer’s disease are major medical issues that affect the health of the elderly population (Yang Y. et al, 2017). Damage to the BBB is an early pathophysiological factor in many diseases. Mfsd2a in Vascular Cognitive Impairment involving brain injury (Daneman and Prat, 2015; Liebner et al, 2018). Previous studies found that BBB damage occurred in the early stage of CCH in rat models (Chen et al, 2015; Yin et al, 2015). Disruption of the BBB caused further structural and functional damage to the brain (Chen et al, 2015; Yin et al, 2015), whereas protective measures targeting the BBB alleviated cognitive impairment in CCH rats (Edrissi et al, 2016; Lee et al, 2017). BBB damage is considered a key factor in CCH-induced cognitive impairment (Ueno et al, 2016)

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Results

Conclusion