title: Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis.
abstract: The apolipoprotein E (APOE)-ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease, likely increasing risk by altering amyloid-β (Aβ) 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 Aβ accumulation by altering Aβ clearance from brain interstitial fluid. We hypothesized that increasing LDLR levels enhances blood-brain barrier-mediated Aβ clearance, thus leading to reduced Aβ accumulation. Using the brain Aβ efflux index method, we found that blood-brain barrier-mediated clearance of exogenously administered Aβ is enhanced with LDLR overexpression. We next developed a method to directly assess the elimination of centrally derived, endogenous Aβ into the plasma of mice using an anti-Aβ antibody that prevents degradation of plasma Aβ, allowing its rate of appearance from the brain to be measured. Using this plasma Aβ accumulation technique, we found that LDLR overexpression enhances brain-to-blood Aβ transport. Together, our results suggest a unique mechanism by which LDLR regulates brain-to-blood Aβ clearance, which may serve as a useful therapeutic avenue in targeting Aβ clearance from the brain.
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Castellano
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gottesdiener
authors.forename: Philip B
authors.initials: PB
authors.lastname: Verghese
authors.forename: Floy R
authors.initials: FR
authors.lastname: Stewart
authors.forename: Tim
authors.initials: T
authors.lastname: West
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Paoletti
authors.forename: Tristan R
authors.initials: TR
authors.lastname: Kasper
authors.forename: Ronald B
authors.initials: RB
authors.lastname: DeMattos
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D000483:Alleles; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000686:Amyloidosis / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics*; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D017551:Microdialysis; D011973:Receptors, LDL / Q000096:biosynthesis*; D019076:Transgenes
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D007328:Insulin; D011973:Receptors, LDL