Role of LDL receptor protein-1 (LRP-1) in Alzheimer's disease

Abstract

Brain endothelial low-density lipoprotein receptor related protein-1 (LRP-1) mediates vascular clearance of Alzheimer's amyloid-β peptide (Aβ) from the brain. Transport of Aβ occurs across the blood-brain barrier (BBB) to the systemic circulation, but the brain endothelium is compromised in Alzheimer's disease. The invention is used to diagnose the disease in symptomatic and asymptomatic individuals, to identify those at risk for disease or already affected thereby, to determine the stage of disease or its progression, to intervene earlier in or alter the disease's natural history, to provide a target for therapeutic or prophylactic treatments, to screen drugs or compare medical regimens, to determine the effectiveness of a drug or medical regimen, or any combination thereof.

What is claimed is:  
     
         1 . A method of at least diagnosing an individual with Alzheimer's disease or identifying an individual as being at risk for developing Alzheimer's disease, said method comprising: 
 (a) measuring at least abundance of low-density lipoprotein receptor related protein-1 (LRP-1), abundance of transcripts thereof, or LRP-1 receptor activity in an individual,    (b) comparing the abundance of LRP-1 protein, abundance of transcripts thereof, or activity of LRP-1 receptor in said individual to at least one control, and    (c) at least diagnosing said individual with Alzheimer's disease or identifying said individual as being at risk for developing Alzheimer's disease when the abundance of LRP-1 protein, abundance of transcripts thereof, or activity of LRP-1 receptor in said individual is decreased relative to said control.    
     
     
         2 . The method of  claim 1 , wherein the abundance of LRP-1 protein, abundance of transcripts thereof, or activity of LRP-1 receptor is measured at least in a brain vascular or systemic endothelial cell of said individual.  
     
     
         3 . The method of  claim 1 , wherein the abundance of LRP-1 protein, abundance of transcripts thereof, or activity of LRP-1 receptor is measured at least in a brain capillary, a temporal artery, a leptomeningeal artery, or at the blood-brain barrier of said individual.  
     
     
         4 . The method of  claim 1 , wherein said at least one control is a value indicative of increased risk for developing Alzheimer's disease and/or a value indicative of decreased risk for developing Alzheimer's disease.  
     
     
         5 . A method of at least treating an individual with Alzheimer's disease or at risk for developing Alzheimer's disease, said method comprising increasing low-density lipoprotein receptor related protein-1 (LRP-1) mediated removal of amyloid-β peptide (Aβ) at the blood-brain barrier in said individual in the direction from brain to blood.  
     
     
         6 . The method of  claim 5 , wherein removal of Aβ is increased by increasing at least LRP-1 expression or receptor activity.  
     
     
         7 . The method of  claim 5 , wherein removal of Aβ is increased by increasing at least expression of a ligand of LRP-1 or transport of said ligand.  
     
     
         8 . The method of  claim 7 , wherein said ligand of LRP-1 is apolipoprotein E.  
     
     
         9 . The method of  claim 7 , wherein said ligand of LRP-1 is α 2 -macroglobulin.  
     
     
         10 . The method of  claim 7 , wherein LRP-1 mediated removal of Aβ is increased by administering at least one proteasome inhibitor.  
     
     
         11 . A method of at least treating an individual with Alzheimer's disease or at risk for developing Alzheimer's disease, said method comprising increasing vascular clearance of amyloid-β peptide (Aβ) from the brain of said individual.  
     
     
         12 . The method of  claim 11 , wherein vascular permeability to Aβ is increased.  
     
     
         13 . The method of  claim 11 , wherein at least angiogenesis or neovasularization in the brain is increased.  
     
     
         14 . A method of determining the effectiveness of at least a drug or medical regimen for treating Alzheimer's disease, said method comprising: 
 (a) measuring the abundance of low-density lipoprotein receptor related protein-1 (LRP-1), abundance of transcripts thereof, or activity of LRP-1 receptor in the presence of said drug or medical regimen, and    (b) at least determining said drug or medical regimen is effective when the abundance of LRP-1 protein, abundance of transcripts thereof, or activity of LRP-1 receptor is increased in the presence of said drug or medical regimen.    
     
     
         15 . The method of  claim 14  further comprising decreasing said abundance of LRP-1, abundance of transcripts thereof, or activity of LRP-1 receptor prior to treatment.  
     
     
         16 . The method of  claim 15 , wherein said abundance of LRP-1, abundance of transcripts thereof, or activity of LRP-1 receptor is decreased by at least one soluble amyloid-β peptide (Aβ) and/or aggregate thereof.  
     
     
         17 . A novel drug or use of a medical regimen for treating Alzheimer's disease determined to be effective by the method of  claim 14 .  
     
     
         18 . The drug or use of a medical regimen of  claim 17  which comprises a proteasome inhibitor.  
     
     
         19 . A kit comprised of one or more of a specific binding molecule for low-density lipoprotein receptor related protein-1 (LRP-1) or a transcript thereof used to measure abundance of said LRP-1 protein, abundance of transcripts thereof, or LRP-1 receptor activity, and/or a non-Alzheimer's disease control containing LRP-1 protein or a transcript thereof.