Abstract
The pathogenesis of Alzheimers disease (AD) involves the abnormal accumulation and deposition of β- amyloid in cerebral blood vessels and in the brain parenchyma. Critical in modulating β-amyloid deposition in brain is the flux of Aβ across the blood brain barrier. The low-density lipoprotein receptor-related protein (LRP), is a large endocytic receptor that mediates the efflux of Aβ out of brain and into the periphery. The first step in the LRP-mediated clearance of Ab involves the formation of a complex between Aβ and the LRP ligands apolipoprotein E (apoE) or α2-macroglobulin (α2M). The Aβ / chaperone complexes then bind to LRP via binding sites on apoE or α2M. The efflux of Aβ / chaperone complexes out of the neuropil and into the periphery may be attenuated by LRP-ligands that compete with apoE or α2M for LRP binding. LRP is also the cell surface receptor for Kunitz Protease Inhibitor (KPI) containing isoforms of Abs parent protein, the amyloid protein precursor (APP). Protein and mRNA levels of KPI-containing APP isoforms (APP-KPI) are elevated in AD brain and are associated with increased Ab production. In this study we show that soluble non-amyloidogenic APP-KPI can also inhibit the uptake of Aβ / α2M in a cell culture model of LRP mediated Aβ clearance. Clearance of Aβ / apoE complexes was not inhibited by APP-KPI. Our findings are consistent with studies showing that apoE and α2M have discrete binding sites on LRP. Most significantly, our data suggests that the elevated levels of APP-KPI in AD brain may attenuated the clearance of Aβ, the proteins own amyloidogenic catabolic product.
Keywords: alzheimers disease, clearance, low density lipoprotein receptor-related protein, apolipoprotein e, macroglobulin, amyloid protein precursor
Current Alzheimer Research
Title: LRP-Mediated Clearance of Aβ is Inhibited by KPI-Containing Isoforms of APP
Volume: 2 Issue: 2
Author(s): Robert D. Moir and Rudolph E. Tanzi
Affiliation:
Keywords: alzheimers disease, clearance, low density lipoprotein receptor-related protein, apolipoprotein e, macroglobulin, amyloid protein precursor
Abstract: The pathogenesis of Alzheimers disease (AD) involves the abnormal accumulation and deposition of β- amyloid in cerebral blood vessels and in the brain parenchyma. Critical in modulating β-amyloid deposition in brain is the flux of Aβ across the blood brain barrier. The low-density lipoprotein receptor-related protein (LRP), is a large endocytic receptor that mediates the efflux of Aβ out of brain and into the periphery. The first step in the LRP-mediated clearance of Ab involves the formation of a complex between Aβ and the LRP ligands apolipoprotein E (apoE) or α2-macroglobulin (α2M). The Aβ / chaperone complexes then bind to LRP via binding sites on apoE or α2M. The efflux of Aβ / chaperone complexes out of the neuropil and into the periphery may be attenuated by LRP-ligands that compete with apoE or α2M for LRP binding. LRP is also the cell surface receptor for Kunitz Protease Inhibitor (KPI) containing isoforms of Abs parent protein, the amyloid protein precursor (APP). Protein and mRNA levels of KPI-containing APP isoforms (APP-KPI) are elevated in AD brain and are associated with increased Ab production. In this study we show that soluble non-amyloidogenic APP-KPI can also inhibit the uptake of Aβ / α2M in a cell culture model of LRP mediated Aβ clearance. Clearance of Aβ / apoE complexes was not inhibited by APP-KPI. Our findings are consistent with studies showing that apoE and α2M have discrete binding sites on LRP. Most significantly, our data suggests that the elevated levels of APP-KPI in AD brain may attenuated the clearance of Aβ, the proteins own amyloidogenic catabolic product.
Export Options
About this article
Cite this article as:
Moir D. Robert and Tanzi E. Rudolph, LRP-Mediated Clearance of Aβ is Inhibited by KPI-Containing Isoforms of APP, Current Alzheimer Research 2005; 2 (2) . https://dx.doi.org/10.2174/1567205053585918
DOI https://dx.doi.org/10.2174/1567205053585918 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Gauging Reactive Metabolites in Drug-Induced Toxicity
Current Medicinal Chemistry Neuropeptide Receptors in Intestinal Disease: Physiology and Therapeutic Potential
Current Pharmaceutical Design Correlates of Physical Activity of Children and Adolescents with Visual Impairments: A Systematic Review
Current Pharmaceutical Design Radiosyntheses using Fluorine-18: The Art and Science of Late Stage Fluorination
Current Topics in Medicinal Chemistry Discovery of Notch-Sparing γ-Secretase Inhibitors
Current Alzheimer Research The Underestimated Role of Mechanical Stimuli in Brain Diseases and the Relate d In Vitro Models
Current Pharmaceutical Design Molecularly Imprinted Sol-Gel Materials for Medical Applications
Current Topics in Medicinal Chemistry Effect of Simultaneous Snail Slime-aided Degradation and Yeast Fermentation on Terpenoid Composition of Plantain Pseudostem Waste
Current Pharmaceutical Biotechnology Protein Kinase C Pharmacology: Perspectives on Therapeutic Potentials as Antidementic and Cognitive Agents
Recent Patents on CNS Drug Discovery (Discontinued) Cancer Vaccines for Hormone/Growth Factor Immune Deprivation:A Feasible Approach for Cancer Treatment
Current Cancer Drug Targets Antioxidants and Neuroprotection in the Adult and Developing Central Nervous System
Current Medicinal Chemistry Rapid Improvement of Canine Cognitive Dysfunction with Immunotherapy designed for Alzheimer's Disease
Current Alzheimer Research Systemic Autoimmune Manifestations: When Should Underlying Thyroid Autoimmunity be Considered?
Current Rheumatology Reviews Kappa Receptor Bivalent Ligands
Current Topics in Medicinal Chemistry Preventing Child and Adolescent Mental Illness - We Got This
Adolescent Psychiatry Complex Obesity
Current Pediatric Reviews Editorial [Hot topic: Current Approaches for the Treatment of Cognitive Deficits in CNS Disease (Guest Editor: Robert L. Hudkins)]
Current Topics in Medicinal Chemistry Rheumatological Diseases in HIV Infection
Current Rheumatology Reviews Expectancy and the Treatment of Depression: A Review of Experimental Methodology and Effects on Patient Outcome
Current Psychiatry Reviews Preface
CNS & Neurological Disorders - Drug Targets