Presenter of 1 Presentation
MOLECULAR PATHWAYS DRIVING SEX-DEPENDENT VULNERABILITY TO BLOOD-BRAIN BARRIER DYSFUNCTION IN ALZHEIMER'S BRAIN
Abstract
Aims
Objective: To determine BBB dysfunction in female versus male Alzheimer’s disease (AD) patients and transgenic mice.
Methods
Gene expression data from male and female AD patients (ROSMAP, APOE33) was obtained. Differential gene expression and data-driven pathway analysis was conducted. The impact of genes and pathways, thus identified, on the BBB integrity and function was assessed using SPECT/CT and PET/CT imaging.
Results
Growth factor signaling and inflammatory pathways are differentially expressed in male versus female AD patients. Insulin signaling, MAPK, mTOR pathways are significantly activated in male patients compared to females(FDR<0.05). Moreover, pathways that regulate BBB integrity, tight junctions and cellular adhesion molecules (VCAM1), are activated in male AD patients compared to females. Similar sex-dependent changes were also observed in APP/PS1 mice but not in wild type controls. Disruption of BBB integrity as determined by increased luminal-to-abluminal permeability of 125I-Albumin as well as 125I-Abeta42, and higher binding of 125I-VCAM1 antibody to the BBB endothelium was observed in female APP/PS1 mice than in male mice. Moreover, selectivity of BBB transport represented by luminal-to-abluminal transport of 18FDG and 125I-Insulin as well as the abluminal-to-luminal clearance of 125I-Abeta42 is more disrupted in female mice compared to male mice.
Conclusions
Growth factor signaling pathways are activated in males, and inflammatory pathways are activated in female AD patients and APP/PS1 mice. Consequently, loss of BBB integrity and selectivity of BBB transport regulated by these pathways are disrupted in females compared to their male counterparts.