Inhibition of calcium‐dependent phospholipase A2 improves blood‐brain barrier integrity in ApoE4 carrying mice. (20th December 2022)

• Record Type: Journal Article
• Authors: Kerman, Bilal E.; Duro, Marlon Vincent V.; Maria, Naomi Sta.; Liu, Xiaodan; Wang, Shaowei; Van Valkenburgh, Juno S.; Chen, Kai; Jacobs, Russell E.; Yassine, Hussein N.
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.067937
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Blood‐brain barrier (BBB) is essential for neural health and function. Degradation of BBB is observed in Alzheimer's disease (AD) and is more pronounced in individuals carrying the apolipoprotein E4 ( ApoE4 ) allele, which is a major genetic risk factor for AD. ApoE4 increases the activation of calcium‐dependent phospholipase A2 (cPLA2), which is linked to BBB function. Here, we asked if cPLA2 inhibition in ApoE4 carrying mice could repair BBB integrity and if the changes could be observed in vivo by dynamic contrast‐enhanced MRI (DCE‐MRI). Method: 16‐month‐old ApoE4 targeted replacement (ApoE4‐TR) mice were divided into a control group treated with vehicle (n=4) and an experimental group treated with a cPLA2 inhibitor ASB‐14780 (n=4). All imaging was performed using a 7T MRI scanner. DCE‐MRI protocol involved acquisition of baseline images (5min), mice receiving a bolus of gadolinium diethylenetriaminepentaacetic acid (Gd‐DTPA, 0.3mmol/kg, i.v.)) and followed by post‐bolus scans for 20min. Regions of interest (ROIs), such as the hippocampus and isocortex, were manually defined using T2‐weighted (FSE) anatomical scans in ImageJ. Volume transfer constants (KTrans ) of the contrast agent uptake were calculated for each subject from the dynamic DCE‐MRI scan using the Patlak model on the Rocketship software (MATLAB). Result: KTrans values for the isocortex and the hippocampus were calculated for two animals from the control group and three animals from the experimental group. The mean KTrans value in the hippocampus region was 60% lower for the mice treated with cPLA2 inhibitor than controls (p=0.056), 0.0459 ± 0.0168 min ‐1 and 0.117 ± 0.030 min ‐1 respectively. Similarly, the mean KTrans value in the isocortex for the treated mice was 50% lower than the controls (p=0.89), 0.0554 ± 0.018 min ‐1 and 0.110 ± 0.028 min ‐1 respectively. Conclusion: We observed that cPLA2 inhibition decreased KTrans values implying increased BBB function. Thus, cPLA2 inhibition can be a possible therapeutic path towards reversing some of the damage to the brain due to AD. Currently, we are validating this observation with larger sample sizes and by analyzing the brains of these mice for changes in molecular signatures of BBB.