Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease.
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.
Deane
Rashid
R
Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research, University of Rochester Medical Center, Rochester, NY 14642, USA. Deane@urmc.Rochester.edu
Zlokovic
Berislav V
BV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic