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

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.

In vitro anti-cholinesterase activity and in vivo screening of Coccoloba uvifera, Mimusops elengi and Syzygium aqueum extracts on learning and memory function of chronic cerebral hypoperfusion rat

“…In the present study, the results obtained from behavioural tasks indicate that both the non-spatial (short-and long-term) and spatial memories function were impaired after CCH in rats. These observations are consistent with previous studies in which POBCCA rats demonstrated a deficit in nonspatial and spatial memories (Hu et al, 2017;Sohn et al, 2019;Yao et al, 2019;Qu et al, 2020). The hippocampus plays a vital role in encoding, and newly acquired information is temporarily stored as STM within the hippocampus (Macdonald et al, 2013) before being transmitted to the cerebral cortex for longterm storage (Ivanco & Racine, 2000;Williams et al, 2004;Mehta, 2018).…”

Brain endothelial PTEN/AKT/NEDD4-2/MFSD2A axis regulates blood-brain barrier permeability

“…MFSD2A specifically inhibits caveolae-mediated transcytosis in ECs, and that inhibition largely relies on its lipid-transporter function. Consistently, recent studies have revealed that Mfsd2a overexpression can efficiently suppress caveolae-mediated transcytosis and attenuate BBB dysfunction (Eser Ocak et al, 2020;Qu et al, 2020). Of note, MFSD2A decease and transcytosis increase are implicated in the pathophysiological processes of BBB breakdown and neurological abnormalities (Yang et al, 2020).…”

Blood–Brain Barrier Dysfunction and the Potential Mechanisms in Chronic Cerebral Hypoperfusion Induced Cognitive Impairment

“…The TJ-related protein, ZO-1, was found to be downregulated in CCH mice, targeted by TNFα–miR-501-3p axis ( Toyama et al, 2018 ). Besides, downregulation of major facilitator superfamily domain-containing protein 2a (Mfsd2a) might cause cognitive impairment in CCH rats by promoting transcytosis in endothelial cells and exacerbating BBB breakdown ( Qu et al, 2020 ).…”