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      Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer’s disease: the role, regulation and restoration of LRP1

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          Abstract

          Amyloid beta (Aβ) homeostasis in the brain is governed by its production and clearance mechanisms. An imbalance in this homeostasis results in pathological accumulations of cerebral Aβ, a characteristic of Alzheimer’s disease (AD). While Aβ may be cleared by several physiological mechanisms, a major route of Aβ clearance is the vascular-mediated removal of Aβ from the brain across the blood-brain barrier (BBB). Here, we discuss the role of the predominant Aβ clearance protein—low-density lipoprotein receptor-related protein 1 (LRP1)—in the efflux of Aβ from the brain. We also outline the multiple factors that influence the function of LRP1-mediated Aβ clearance, such as its expression, shedding, structural modification and transcriptional regulation by other genes. Finally, we summarize approaches aimed at restoring LRP1-mediated Aβ clearance from the brain.

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          Most cited references91

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          Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

          The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
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            RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain.

            Amyloid-beta peptide (Abeta) interacts with the vasculature to influence Abeta levels in the brain and cerebral blood flow, providing a means of amplifying the Abeta-induced cellular stress underlying neuronal dysfunction and dementia. Systemic Abeta infusion and studies in genetically manipulated mice show that Abeta interaction with receptor for advanced glycation end products (RAGE)-bearing cells in the vessel wall results in transport of Abeta across the blood-brain barrier (BBB) and expression of proinflammatory cytokines and endothelin-1 (ET-1), the latter mediating Abeta-induced vasoconstriction. Inhibition of RAGE-ligand interaction suppresses accumulation of Abeta in brain parenchyma in a mouse transgenic model. These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis.
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              Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.

              Two substrates of insulin-degrading enzyme (IDE), amyloid beta-protein (Abeta) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of Abeta levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases Abeta and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE --). IDE deficiency resulted in a >50% decrease in Abeta degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE -- mice showed increased cerebral accumulation of endogenous Abeta, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                15 July 2015
                2015
                : 7
                : 136
                Affiliations
                [1]Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California Los Angeles, CA, USA
                Author notes

                Edited by: Roxana Octavia Carare, University of Southampton, UK

                Reviewed by: Ignacio Torres-Aleman, Cajal Institute, Spain; Robert Marr, Rosalind Franklin University of Medicine and Science, USA; Stéphane Dedieu, CNRS UMR 7369 MEDYC and Reims University, France

                *Correspondence: Berislav V. Zlokovic, Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90089, USA zlokovic@ 123456usc.edu
                Article
                10.3389/fnagi.2015.00136
                4502358
                26236233
                c9d0abbe-a20f-4c85-88e3-05aac131f4c1
                Copyright © 2015 Ramanathan, Nelson, Sagare and Zlokovic.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 June 2015
                : 02 July 2015
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 135, Pages: 12, Words: 10304
                Funding
                Funded by: National Institutes of Health
                Award ID: AG039452
                Award ID: AG23084
                Award ID: NS34467
                Funded by: Zilkha Senior Scholar Support
                Categories
                Neuroscience
                Review

                Neurosciences
                amyloid β clearance,blood-brain barrier,lipoprotein receptor-related protein 1 (lrp1),picalm,alzheimer’s disease (ad)

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