title: Endothelial LRP1 transports amyloid-β(1-42) across the blood-brain barrier.
abstract: According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor-related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-β (Aβ) brain accumulation and drives Alzheimer's disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in Aβ transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic Aβ clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slco1c1-CreER(T2) Lrp1(fl/fl) mice) and used these mice to accurately evaluate LRP1-mediated Aβ BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [125I] Aβ(1-42). Additionally, in the 5xFAD mouse model of AD, brain endothelial-specific Lrp1 deletion reduced plasma Aβ levels and elevated soluble brain Aβ, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic Aβ elimination via the BBB. Together, our results suggest that receptor-mediated Aβ BBB clearance may be a potential target for treatment and prevention of Aβ brain accumulation in AD.
authors.forename: Steffen E
authors.initials: SE
authors.lastname: Storck
authors.forename: Sabrina
authors.initials: S
authors.lastname: Meister
authors.forename: Julius
authors.initials: J
authors.lastname: Nahrath
authors.forename: Julius N
authors.initials: JN
authors.lastname: Meißner
authors.forename: Nils
authors.initials: N
authors.lastname: Schubert
authors.forename: Alessandro
authors.initials: A
authors.lastname: Di Spiezio
authors.forename: Sandra
authors.initials: S
authors.lastname: Baches
authors.forename: Roosmarijn E
authors.initials: RE
authors.lastname: Vandenbroucke
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Bouter
authors.forename: Ingrid
authors.initials: I
authors.lastname: Prikulis
authors.forename: Carsten
authors.initials: C
authors.lastname: Korth
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.forename: Axel
authors.initials: A
authors.lastname: Heimann
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.forename: Claus U
authors.initials: CU
authors.lastname: Pietrzik
mesh_terms: D016229:Amyloid beta-Peptides / Q000493:pharmacokinetics*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology; D042783:Endothelial Cells / Q000502:physiology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000493:pharmacokinetics*; D021381:Protein Transport; D011973:Receptors, LDL / Q000502:physiology*; D057900:Transcytosis; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010446:Peptide Fragments; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C075222:amyloid beta-protein (1-42)