Abstract
Abstract: :
Purpose: Various neuro–degenerative diseases such as Age–Related Macula Degeneration (AMD), have a vascular component. Blood–brain and retina barrier permeability is an important determinant of the vascular integrity in these organs. This study elucidates the impact of aging on blood–brain barrier (BBB) permeability and examines the role of leukocytes therein. Methods: To measure protein leakage, mice were injected intraperitoneally with Evans Blue dye 3 hours prior to tissue collection. Various tissues, including retina and brain, were harvested and the dye was extracted with formamide over 72 hours and quantified by spectrophotometry. Antigen expression on murine leukocytes was detected by flow cytometry. To create chimeric mice, bone marrow transplantation into lethally irradiated hosts was performed. Adherent leukocytes to various tissues were visualized by histology. Results: In wild type mice a significant increase in the permeability of BBB with age (r2=0.27, P<0.01) was found. ApoE–/– mice, however, show an exacerbated age–related increase in their BBB–permeability (r2=0.8, P<0.01). Mice deficient for adhesion molecules involved in inflammatory leukocyte recruitment (ICAM–1–/–, CD18–/–, P–selectin–/–) showed a significantly lower age–related vascular permeability compared to wild type. Leukocytes obtained from ApoE–/– mice expressed an increased amount of inflammatory markers compared to leukocytes from wild type animals, suggesting a higher baseline inflammatory ‘alert status’ in these mice. Chimeric mice with ApoE–/– peripheral leukocytes showed a significantly lower age–related vascular permeability than ApoE–/– mice. The number of adherent leukocytes in histological sections obtained from these animals correlated with their vascular permeability. Conclusions: Our data suggest the existence of a physiologic constitutive inflammatory process that leads to a compromise of vascular integrity with age. This process may mechanistically precede the genesis of age–related neuro–degenerative diseases, such as AMD.
Keywords: aging • inflammation • age–related macular degeneration