| First Author | Hawkes CA | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 7 | Pages | e41636 |
| PubMed ID | 22848551 | Mgi Jnum | J:189699 |
| Mgi Id | MGI:5446863 | Doi | 10.1371/journal.pone.0041636 |
| Citation | Hawkes CA, et al. (2012) Disruption of arterial perivascular drainage of amyloid-beta from the brains of mice expressing the human APOE epsilon4 allele. PLoS One 7(7):e41636 |
| abstractText | Failure of elimination of amyloid-beta (Abeta) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) epsilon4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE epsilon4 allele is associated with disruption of perivascular drainage of Abeta from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3 (TRE3) or APOE4 (TRE4) genes and wildtype mice received intracerebral injections of human Abeta(40). Abeta(40) aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Abeta deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Abeta was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV 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. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Abeta from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature. |
