Type II diabetes mellitus and aging induce blood-brain barrier leakage

R. Loiola, G. Purvis, C. Thiemermann, E. Solito. William Harvey Research Institute, Queen Mary University of London, London, UNITED KINGDOM.

Introduction: The aging process is known to cause specific cardiovascular changes that impair heart and blood vessel function. These changes lead not only to reduced physical and mental ability, but getting older is also a major risk factor for traumatic injuries, sepsis, stroke and diabetes type 2 (T2DM). Various epidemiological studies strongly suggest that these diseases are more often diagnosed in older people than they are in the younger population. Within the brain the blood brain barrier (BBB) composed of an interdependent network of endothelial cells, pericytes, astrocyte end feet and perivascular macrophages, is designed to segregate the central nervous system (CNS) from systemic circulating cells and molecules. Recently, some studies have suggested that chronic low-grade inflammation associated to type II diabetes mellitus (T2DM) has deleterious effects on structure, organization and permeability of BBB. Low grade inflammation is also a future in aging. Although aging is positively associated to increased risk to neurodegenerative disorders, the effect of aging on BBB function still remain unclear. The present project was designed in order to evaluate the effects of aging and T2DM on BBB integrity.

Method: For assessment of T2DM effects on BBB function, C57/bl6 mice, 4 week old, male, were fed with high fat diet (HFD group), a model of experimental T2DM, or chow diet (Chow group), for 10 weeks. For assessment of aging effects on BBB function, C57/bl6 mice, male, young (14 weeks old) and aged (34 weeks old and 60 weeks old) BBB leakage were compared. BBB permeability was determined by evaluating Evans Blue (EB) dye extravasation to brain parenchyma. Data represents mean ± SEM. Analysis was performed using ANOVA or Student’s T test, as applicable. *P<0.05.

Results: HFD-induced T2DM significantly increased BBB permeability (Chow 0.0052 ± 0.00029 vs HFD 0.0195 ± 0.00240*). Aged mice (34 weeks old and 60 weeks old) was also positively associated to increase in BBB permeability (Mice 14 weeks old 0.01127 ± 0.001445 vs 34 weeks old 0.02487 ± 0.001808* vs 60 weeks old 0.00375 ± 0.00299*).

Conclusions: Our data suggest that T2DM accelerate the onset of BBB dysfunction occurring with aging resulting as a consequence of inflammation and disruption of essential component of the BBB named occludin and laminin.