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
Alzheimer's Disease Drug Development
Alzheimer's disease is a progressive neurodegenerative disorder that affects millions of people worldwide. Despite decades of research, no cure or disease-modifying treatment is available yet. Therefore, the need for developing effective therapies to treat Alzheimer's disease is an urgent matter. This special issue aims to provide a comprehensive overview of ...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
- 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 & Future Therapies of Erectile Dysfunction in Neurological Disorders
Recent Patents on CNS Drug Discovery (Discontinued) Biotechnological Engineering of Heparin/Heparan Sulphate: A Novel Area of Multi-Target Drug Discovery
Current Pharmaceutical Design Alzheimers Disease: Targets For Drug Development
Mini-Reviews in Medicinal Chemistry Endothelial Microparticles: Mediators or Markers of Endothelial Cell Dysfunction?
Current Hypertension Reviews The Prion-like Properties of Amyloid-beta Peptide and Tau: Is there Any Risk of Transmitting Alzheimer's Disease During Neurosurgical Interventions?
Current Alzheimer Research Hematologic Abnormalities in the Antiphospholipid Syndrome
Current Rheumatology Reviews Cerebrovascular Complications After Heart Transplantation
Current Cardiology Reviews Regeneration in a Degenerating Brain: Potential of Allopregnanolone as a Neuroregenerative Agent
Current Alzheimer Research What is Tobacco Smoke? Sociocultural Dimensions of the Association with Cardiovascular Risk
Current Pharmaceutical Design Glycoconjugates: Roles in Neural Diseases Caused by Exogenous Pathogens
CNS & Neurological Disorders - Drug Targets 1,2,4-Triazine Analogs as Novel Class of Therapeutic Agents
Mini-Reviews in Medicinal Chemistry Green Synthesis of Phosphoryl-2-Oxo-2H-Pyran via Three Component Reaction of Trialkyl Phosphites
Combinatorial Chemistry & High Throughput Screening Role of Transcranial Doppler Ultrasonography in Cerebrovascular Disease
Recent Patents on CNS Drug Discovery (Discontinued) Sigma-1 Receptors: Potential Targets for the Treatment of Substance Abuse
Current Pharmaceutical Design Development of Small-Molecule Inhibitors of Raf
Recent Patents on Anti-Infective Drug Discovery Drusen in the Peripheral Retina of the Alzheimer’s Eye
Current Alzheimer Research Endothelial Dysfunction Induced by Cadmium and Mercury and its Relationship to Hypertension
Current Hypertension Reviews Cognitive Event-Related Potentials: Useful Clinical Information in Alzheimers Disease
Current Alzheimer Research Autophagy in the Central Nervous System: Implications for Neurodegenerative Disorders
CNS & Neurological Disorders - Drug Targets Adrenomedullin Expression in Alzheimer's Brain
Current Alzheimer Research