Testing the Neurovascular Hypothesis of Alzheimer's Disease: LRP-1 Antisense Reduces Blood-brain Barrier Clearance, Increases Brain Levels of Amyloid-β Protein, and Impairs Cognition

Article type: Research Article

Authors: Jaeger, Laura B.^{a; b} | Dohgu, Shinya^{b; c} | Hwang, Mark C.^{b; c} | Farr, Susan A.^{b; c} | Murphy, M. Paul^d | Fleegal-DeMotta, Melissa A.^{b; c} | Lynch, Jessica L.^{b; c} | Robinson, Sandra M.^{b; c} | Niehoff, Michael L.^{b; c} | Johnson, Steven N.^{b; c} | Kumar, Vijaya B.^{b; c} | Banks, William A.^{a; b; c; *}

Affiliations: [a] Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO, USA | [b] Geriatric Research Education and Clinical Center (GRECC), VA Medical Center, St. Louis, MO, USA | [c] Department of Internal Medicine, Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA | [d] Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA

Correspondence: [*] Corresponding author: William A. Banks, MD, VAMC, 915 N. Grand Blvd, St. Louis, MO 63106, USA. Tel.: 314 289 7084; Fax: 314 289 6374; E-mail: [email protected].

Abstract: Decreased clearance is the main reason amyloid-β protein (Aβ) 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 Aβ 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 Aβ42, increased brain levels of Aβ42, 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 Aβ could increase and AD would be promoted.

Keywords: Alzheimer's disease, antisense, blood-brain barrier, cognition, low density lipoprotein receptor related protein-1 (LRP-1), learning, memory, transporter

DOI: 10.3233/JAD-2009-1074

Journal: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 553-570, 2009