| First Author | Castellano JM | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 38 | Pages | 15502-7 |
| PubMed ID | 22927427 | Mgi Jnum | J:190030 |
| Mgi Id | MGI:5447866 | Doi | 10.1073/pnas.1206446109 |
| Citation | Castellano JM, et al. (2012) Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Abeta clearance in a mouse model of beta-amyloidosis. Proc Natl Acad Sci U S A 109(38):15502-7 |
| abstractText | The apolipoprotein E (APOE)-epsilon4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-beta (Abeta) accumulation. We recently demonstrated that the low-density lipoprotein receptor (LDLR) is a major apoE receptor in the brain that strongly regulates amyloid plaque deposition. In the current study, we sought to understand the mechanism by which LDLR regulates Abeta accumulation by altering Abeta clearance from brain interstitial fluid. We hypothesized that increasing LDLR levels enhances blood-brain barrier-mediated Abeta clearance, thus leading to reduced Abeta accumulation. Using the brain Abeta efflux index method, we found that blood-brain barrier-mediated clearance of exogenously administered Abeta is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous Abeta into the plasma of mice using an anti-Abeta antibody that prevents degradation of plasma Abeta, allowing its rate of appearance from the brain to be measured. Using this plasma Abeta accumulation technique, we found that LDLR overexpression enhances brain-to-blood Abeta transport. Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood Abeta clearance, which may serve as a useful therapeutic avenue in targeting Abeta clearance from the brain. |
