Microglia and macrophages derived from transgenic mice expressing human apoE4 have altered cell morphology, higher production of pro-inflammatory cytokines and are less efficient at degrading Ab than those from apoE2 and apoE3 mice. In addition, binding of Ab to apoE has been shown to redirect transport across the blood-brain barrier in an isoform specific manner, towards slower clearance via very low density lipoprotein receptors. However, little is known about the putative effect of apoE genotype on the elimination of Ab from the brain along vascular basement membranes. collagen IV, nidogens and heparan sulfate proteoglycans such as perlecan and agrin. Basement membranes regulate endothelial and smooth muscle cell growth, differentiation and migration and are proposed to be an important pathway for the efflux of ISF from the brain. Previous studies have demonstrated that solutes injected into the murine brain colocalize with basement membranes in the walls of capillaries and arteries. Further, solute diffusion occurs rapidly and is detected in capillary walls within 5 minutes of injection and within perivascular macrophages at 30 minutes post-injection. Changes in basement membrane expression and morphology are observed in the vasculature of the aging and AD brain and result in the disturbed elimination of solutes from the parenchyma and the development of CAA. Furthermore, laminin, collagen IV, nidogen, agrin and perlecan, can interact directly with Ab and influence its aggregation. There is also evidence to suggest that apoE mediates the interaction between Ab and basement membrane proteins. In vitro experiments have shown that laminin binds apoE and inhibits Ab40 fibril formation induced by apoE4. ApoE and Ab colocalize in the INCB18424 cerebral vasculature of mouse and AD brains and a significant reduction in the surface area of agrin immunoreactivity has been reported previously in the brains of AD individuals homozygous for the APOE4 allele. In addition, recent findings from transgenic PDAPP mice expressing human apoE4 have demonstrated elevated levels of soluble Ab within their cerebral ISF, without increased Ab production, suggesting the possible influence of apoE on the perivascular drainage of Ab from the brain. Therefore, in the present study, we tested the hypothesis that the presence of human apoE3 and apoE4 isoforms differentially affects the level of cerebrovascular basement membranes and the pattern of perivascular drainage of Ab from the adult mouse brain. We found that the pattern of Ab40 distribution following injection into the hippocampus was significantly disrupted in the arterial walls of 3- and 16-month old TRE4 animals, but not in TRE3 or wildtype mice. Further, analysis of vascular basement membrane protein levels showed increased collagen IV levels in 3-month old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. These results suggest that expression of apoE4 may promote Ab accumulation in AD in part by modifying the expression of cerebral vascular basement membrane proteins and disrupting the efficiency of perivascular drainage of Ab from the brain. Due to technical difficulties in achieving adequate antigen retrieval for agrin immunocytochemistry, an anti-perlecan antibody was used as a marker of heparan sulfate proteoglycans. Consistent with the Western blot data, increased staining intensity for laminin in the basement membranes of capillaries was noted in both 3-month old TRE3 and TRE4 mice compared to age-matched wildtype mice.