Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis

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