In a transgenic mouse carrying human APOE4 (a major genetic risk factor for AD), APOE4 secreted from astrocytes was found to bind with LRP1 on pericytes and induce uncontrollably proinflammatory CypA expression in pericytes, inducing the activation of NF-kB and matrix metalloproteinase 9 (MMP9),183,501 which has been suggested to be increased in leptomeningeal vessels of AD patients.502 In addition, reduced expression of tight junction proteins was found in AD mouse model with increased MMP9 activities.183 These results explain the mechanism of MMP9 in regulating BBB integrity. This evidence concerns the gene APOE and Alzheimer disease.