Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood A? clearance in a mouse model of ?-amyloidosis.

ABSTRACT: The apolipoprotein E (APOE)-?4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-? (A?) 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 A? accumulation by altering A? clearance from brain interstitial fluid. We hypothesized that increasing LDLR levels enhances blood-brain barrier-mediated A? clearance, thus leading to reduced A? accumulation. Using the brain A? efflux index method, we found that blood-brain barrier-mediated clearance of exogenously administered A? is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous A? into the plasma of mice using an anti-A? antibody that prevents degradation of plasma A?, allowing its rate of appearance from the brain to be measured. Using this plasma A? accumulation technique, we found that LDLR overexpression enhances brain-to-blood A? transport. Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood A? clearance, which may serve as a useful therapeutic avenue in targeting A? clearance from the brain.

SUBMITTER: Castellano JM 

PROVIDER: S-EPMC3458349 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature