Abstract W MP94: Acute Inflammation Expands Cerebral Microbleeds in a Mouse Model of Cerebral Amyloid Angiopathy
Introduction: Cerebral microscopic hemorrhages are the pathologic substrate of cerebral microbleeds (CMB). Little is known about mechanisms of expansion of CMB. Here we studied the dynamics of CMB after acute inflammation, using a transgenic mouse model of cerebral amyloid angiopathy with spontaneous microscopic hemorrhages and endotoxin (lipopolysaccharide, LPS) as an inflammatory stimulus.
Methods: 21-month old Tg2576 mice and wildtype littermates received a single dose of LPS, 100 or 1000 ug/kg i.p., or phosphate-buffered saline (PBS) as control. Mice were sacrificed 48 hours later and brains were collected for the analysis of microscopic hemorrhages, as well as edema formation, blood-brain barrier constituents and glial activation. Differences among groups were tested by anova and contrasts.
Results: Hematoxylin and eosin staining demonstrated no freshly-formed microscopic hemorrhages in LPS-treated mice. Using Prussian blue staining, we found that total area, average size, and number of CMB differed significantly between PBS-treated wildtype and transgenic mice (p=0.03, p=.04 and p=.03 respectively). Acute inflammation did not significantly affect total area, average size, or number of CMB in wildtype animals. For transgenic mice, both doses of LPS significantly (p<.01) increased the total area of Prussian blue-positive lesions (2.2 to 2.9-fold increase), and higher LPS dose significantly (p<.01) increased average size of CMB by 2.6-fold; both average and total size of CMB increased in a dose-dependent manner. IgG and fibrinogen levels significantly increased after high dose LPS injection in both wildtype and transgenic mice (p<.05). Tight junction protein claudin-5 levels were also increased in high dose LPS-treated mice (p<0.05). LPS injection significantly increased expression of activated microglia markers CD45, CD14, and Iba1.
Conclusions: In a mouse model of cerebral amyloid angiopathy, acute inflammatory stimulus induced expansion of CMB without producing fresh hemorrhage. Increased size of CMB was associated with indices of cerebral edema, alteration of tight junction constituents, and microglial activation. These findings suggest that cerebral edema may mediate expansion of cerebral microbleeds.
Author Disclosures: V. Vasilevko: None. M.J. Fisher: None. K. Kilday: None. G.F. Passos: None. S. Liu: None. R.C. Kim: None. A. Paganini-Hill: None. D.H. Cribbs: None.
- © 2014 by American Heart Association, Inc.