Testing the neurovascular hypothesis of Alzheimer's disease: LRP-1 antisense reduces blood-brain barrier clearance, increases brain levels of amyloid-beta protein, and impairs cognition.
Decreased clearance is the main reason amyloid-beta protein (Abeta) is increased in the brains of patients with Alzheimer's disease (AD). The neurovascular hypothesis states that this decreased clearance is caused by impairment of low density lipoprotein receptor related protein-1 (LRP-1), the major brain-to-blood transporter of Abeta at the blood-brain barrier (BBB). As deletion of the LRP-1 gene is a lethal mutation, we tested the neurovascular hypothesis by developing a cocktail of phosphorothioate antisenses directed against LRP-1 mRNA. We found these antisenses in comparison to random antisense selectively decreased LRP-1 expression, reduced BBB clearance of Abeta42, increased brain levels of Abeta42, and impaired learning ability and recognition memory in mice. These results support dysfunction of LRP-1 at the BBB as a mechanism by which brain levels of Abeta could increase and AD would be promoted.
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO, USA.
Laura B
LB
Jaeger
Shinya
S
Dohgu
Mark C
MC
Hwang
Susan A
SA
Farr
M Paul
MP
Murphy
Melissa A
MA
Fleegal-DeMotta
Jessica L
JL
Lynch
Sandra M
SM
Robinson
Michael L
ML
Niehoff
Steven N
SN
Johnson
Vijaya B
VB
Kumar
William A
WA
Banks
D000544:Alzheimer Disease / Q000150:complications / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000139:chemically induced*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D012044:Regression Analysis; D013873:Thionucleotides / Q000494:pharmacology*; D013997:Time Factors; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D008077:Lipoproteins, LDL; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013873:Thionucleotides; C075222:amyloid beta-protein (1-42)