Similarly, HFS was observed in 55% of phase 2 patients, the proportion of grade

Rupture of amyloid laden vessels is associated with CAA related intracerebral haemorrhage . Levels Ivacaftor VX-770 of soluble AB are also raised in the brain in AD and this correlates with cognitive decline, suggesting that the elimination of soluble AB from the brain may be impaired with age and AD . Trials of im munotherapy for AD in humans were introduced follow ing successful studies in transgenic mice showing that insoluble AB plaques were removed from the brain fol lowing immunization with AB42 . However, des pite the clearance of AB plaques from patients with AD, active immunization seems to increase, rather than de crease, the amount of arterial CAA in both transgenic mice and humans . It appears that AB can be solubilised from plaques but it becomes entrapped in the perivascular drainage pathways manifesting as an in crease in the severity of CAA .<br><br> The dynamics of the events resulting in increased CAA following immuno therapy are not clear but it could reflect either an in creased flow of soluble AB out of the brain in the perivascular drainage pathways, or it may reflect impaired drainage and elimination of soluble AB due to the forma tion of AB anti AB immune complexes. In addition, trials of LBH-589 both active and passive AB antibody therapy in patients with AD have encountered side effects comprising focal abnormalities in cerebral white matter on imaging, suggesting an increasing fluid in the subcortical white matter, again reflecting failure of fluid drainage from the brain . The pathophysiology underlying the side effects of AB immunotherapy are as yet unclear but may be due in part to the effects of immune complexes forming in perivascular drainage pathways.<br><br> In previously published studies, we showed first that when OVA is injected into the mouse brain, LY2109761 supplier it drains rapidly out of the brain along basement membranes in the walls of cerebral capillaries and arteries . Secondly we showed that active immunization with OVA followed by the intracerebral injection of the antigen OVA, resulted in the formation of immune complexes in the brain parenchyma associated with a robust inflammatory response and macrophage activation . In the present study, we first tested the hypothesis that immune complexes form in the interstitial fluid drainage pathways the walls of cerebral arteries of OVA immunized mice following challenge with the antigen.<br><br> Second, we tested the hypothesis that the presence of OVA immune complexes in cerebral artery walls disrupts the perivascu lar lymphatic drainage of soluble tracers from the brain. Methods Animals BALB c mice were originally obtained from Charles River and bred and maintained in local facilities. Animal experiments obtained approval from the local Committee for Ethics at the University of Southampton and were performed under Home Office li cencing. A total number of 75 mice of 6 10 weeks old were used in this study. Active immunization 8 week old Balb c mice were immunized against OVA by intraperitoneal injection of 50 ug OVA in the presence of Alum . Mice received a booster injection of 100 ug OVA in saline at 2, 4 and 6 weeks and 3 days before the intracerebral in jection of OVA.