Tags

Type your tag names separated by a space and hit enter

Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease.

Abstract

Cerebrovascular dysfunction contributes to the cognitive decline and dementia in Alzheimer's disease (AD), and may precede cerebral amyloid angiopathy and brain accumulation of the Alzheimer's neurotoxin, amyloid beta-peptide (Abeta). The blood-brain barrier (BBB) is critical for brain Abeta homeostasis and regulates Abeta 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 Abeta through deregulated LRP1/RAGE-mediated transport, aberrant angiogenesis and arterial dysfunction may initiate neurovascular uncoupling, Abeta 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 Abeta clearance and neurovascular repair, and improve cerebral blood flow. RAGE-based and LRP1-based therapeutic strategies have potential to control brain Abeta in AD, and possibly related familial cerebrovascular beta-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.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research, University of Rochester Medical Center, Rochester, NY 14642, USA. Deane@urmc.Rochester.edu

    Source

    Current Alzheimer research 4:2 2007 Apr pg 191-7

    MeSH

    ATP Binding Cassette Transporter, Subfamily B, Member 1
    Alzheimer Disease
    Amyloid beta-Peptides
    Animals
    Biological Transport
    Blood-Brain Barrier
    Humans
    Low Density Lipoprotein Receptor-Related Protein-1
    Receptor for Advanced Glycation End Products
    Receptors, Immunologic

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Review

    Language

    eng

    PubMed ID

    17430246

    Citation

    Deane, Rashid, and Berislav V. Zlokovic. "Role of the Blood-brain Barrier in the Pathogenesis of Alzheimer's Disease." Current Alzheimer Research, vol. 4, no. 2, 2007, pp. 191-7.
    Deane R, Zlokovic BV. Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Curr Alzheimer Res. 2007;4(2):191-7.
    Deane, R., & Zlokovic, B. V. (2007). Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Current Alzheimer Research, 4(2), pp. 191-7.
    Deane R, Zlokovic BV. Role of the Blood-brain Barrier in the Pathogenesis of Alzheimer's Disease. Curr Alzheimer Res. 2007;4(2):191-7. PubMed PMID: 17430246.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. AU - Deane,Rashid, AU - Zlokovic,Berislav V, PY - 2007/4/14/pubmed PY - 2007/7/11/medline PY - 2007/4/14/entrez SP - 191 EP - 7 JF - Current Alzheimer research JO - Curr Alzheimer Res VL - 4 IS - 2 N2 - Cerebrovascular dysfunction contributes to the cognitive decline and dementia in Alzheimer's disease (AD), and may precede cerebral amyloid angiopathy and brain accumulation of the Alzheimer's neurotoxin, amyloid beta-peptide (Abeta). The blood-brain barrier (BBB) is critical for brain Abeta homeostasis and regulates Abeta 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 Abeta through deregulated LRP1/RAGE-mediated transport, aberrant angiogenesis and arterial dysfunction may initiate neurovascular uncoupling, Abeta 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 Abeta clearance and neurovascular repair, and improve cerebral blood flow. RAGE-based and LRP1-based therapeutic strategies have potential to control brain Abeta in AD, and possibly related familial cerebrovascular beta-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. SN - 1567-2050 UR - https://www.unboundmedicine.com/medline/citation/17430246/Role_of_the_blood_brain_barrier_in_the_pathogenesis_of_Alzheimer's_disease_ L2 - http://www.eurekaselect.com/78012/article DB - PRIME DP - Unbound Medicine ER -