Abstract
Cerebrovascular dysfunction contributes to the cognitive decline and dementia in Alzheimers disease (AD), and may precede cerebral amyloid angiopathy and brain accumulation of the Alzheimers neurotoxin, amyloid β-peptide (Aβ). The blood-brain barrier (BBB) is critical for brain Aβ homeostasis and regulates Aβ transport via two main receptors, the low density lipoprotein receptor related protein 1 (LRP1) and the receptor for advanced glycation end products (RAGE). According to the neurovascular hypothesis of AD, faulty BBB clearance of Aβ through deregulated LRP1/RAGE-mediated transport, aberrant angiogenesis and arterial dysfunction may initiate neurovascular uncoupling, Aβ accumulation, cerebrovascular regression, brain hypoperfusion and neurovascular inflammation. Ultimately these events lead to BBB compromise and chemical imbalance in the neuronal ‘milieu’, and result in synaptic and neuronal dysfunction. Based on the neurovascular hypothesis, we suggest an array of new potential therapeutic approaches that could be developed for AD to reduce neuroinflammation, enhance Aβ clearance and neurovascular repair, and improve cerebral blood flow. RAGE-based and LRP1-based therapeutic strategies have potential to control brain Aβ in AD, and possibly related familial cerebrovascular β-amyloidoses. In addition, we have identified two vascularly restricted genes, GAX (growth arrest-specific homeobox), which controls LRP1 expression in brain capillaries and brain angiogenesis, and MYOCD (myocardin), which controls contractility of cerebral arterial smooth muscle cells and influences cerebral blood flow. These findings provide insights into new pathogenic pathways for the vascular dysfunction in AD and point to new therapeutic targets for AD.
Keywords: RAGE, LRP1, AD, aging, cerebrovascular, amyloid-β, BBB, sLRP
Current Alzheimer Research
Title: Role of the Blood-Brain Barrier in the Pathogenesis of Alzheimers Disease
Volume: 4 Issue: 2
Author(s): Rashid Deane and Berislav V. Zlokovic
Affiliation:
Keywords: RAGE, LRP1, AD, aging, cerebrovascular, amyloid-β, BBB, sLRP
Abstract: Cerebrovascular dysfunction contributes to the cognitive decline and dementia in Alzheimers disease (AD), and may precede cerebral amyloid angiopathy and brain accumulation of the Alzheimers neurotoxin, amyloid β-peptide (Aβ). The blood-brain barrier (BBB) is critical for brain Aβ homeostasis and regulates Aβ transport via two main receptors, the low density lipoprotein receptor related protein 1 (LRP1) and the receptor for advanced glycation end products (RAGE). According to the neurovascular hypothesis of AD, faulty BBB clearance of Aβ through deregulated LRP1/RAGE-mediated transport, aberrant angiogenesis and arterial dysfunction may initiate neurovascular uncoupling, Aβ accumulation, cerebrovascular regression, brain hypoperfusion and neurovascular inflammation. Ultimately these events lead to BBB compromise and chemical imbalance in the neuronal ‘milieu’, and result in synaptic and neuronal dysfunction. Based on the neurovascular hypothesis, we suggest an array of new potential therapeutic approaches that could be developed for AD to reduce neuroinflammation, enhance Aβ clearance and neurovascular repair, and improve cerebral blood flow. RAGE-based and LRP1-based therapeutic strategies have potential to control brain Aβ in AD, and possibly related familial cerebrovascular β-amyloidoses. In addition, we have identified two vascularly restricted genes, GAX (growth arrest-specific homeobox), which controls LRP1 expression in brain capillaries and brain angiogenesis, and MYOCD (myocardin), which controls contractility of cerebral arterial smooth muscle cells and influences cerebral blood flow. These findings provide insights into new pathogenic pathways for the vascular dysfunction in AD and point to new therapeutic targets for AD.
Export Options
About this article
Cite this article as:
Deane Rashid and Zlokovic V. Berislav, Role of the Blood-Brain Barrier in the Pathogenesis of Alzheimers Disease, Current Alzheimer Research 2007; 4 (2) . https://dx.doi.org/10.2174/156720507780362245
DOI https://dx.doi.org/10.2174/156720507780362245 |
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
-
Current Advances in Vehicles for Brain Gene Delivery
Current Gene Therapy Hsp20 Protects Neuroblastoma Cells from Ischemia/Reperfusion Injury by Inhibition of Apoptosis via a Mechanism that Involves the Mitochondrial Pathways
Current Neurovascular Research Ischemic and Oxidative Damage to the Hypothalamus May Be Responsible for Heat Stroke
Current Neuropharmacology Role of Physician Gender in the Quality of Care of Cardiometabolic Diseases
Current Pharmaceutical Design The Metabolic Syndrome and HIV Infection
Current Pharmaceutical Design Cholinotrophic Molecular Substrates of Mild Cognitive Impairment in the Elderly
Current Alzheimer Research Editorial [Progress of “Current Alzheimer Research” and Future Direction]
Current Alzheimer Research Lipoprotein (a) Evolution: Possible Benefits and Harm. Genetic and Non-Genetic Factors Influencing its Plasma Levels
Current Medicinal Chemistry Pre-Dementia Diagnosis of Alzheimers Disease: Translating Clinicobiologic Research into Practice
Current Psychiatry Reviews Polypharmacology in a Single Drug: Multitarget Drugs
Current Medicinal Chemistry Synthesis and Evaluation of Chalcone and its Derivatives as Potential Anticholinergic Agents
Letters in Drug Design & Discovery BACE Inhibitors as Potential Therapeutics for Alzheimers disease
Recent Patents on CNS Drug Discovery (Discontinued) 1, 2-Benzisoxazole: A Privileged Structure with a Potential for Polypharmacology
Current Pharmaceutical Design Understanding the Role of Hypoxia Inducible Factor During Neurodegeneration for New Therapeutics Opportunities
Current Neuropharmacology C. elegans as a Genetic Model System to Identify Parkinson's Disease- Associated Therapeutic Targets
CNS & Neurological Disorders - Drug Targets In Silico Ligand-Receptor Docking of Potentially Selective Butyrylcholinesterase Inhibitors Structurally Related to the Marine Natural Product Debromoflustramine B
Medicinal Chemistry Alzheimers Disease: SPECT and PET Tracers for Beta-Amyloid Imaging
Current Alzheimer Research Tau-Focused Immunotherapy for Alzheimers Disease and Related Tauopathies
Current Alzheimer Research Vitamin-mediated immune regulation in the development of inflammatory diseases
Endocrine, Metabolic & Immune Disorders - Drug Targets Schiff Bases of Isatin: Inhibitory Potential Towards Acetylcholinesterase and Butyrylcholinesterase
Letters in Drug Design & Discovery