Role of the Blood-Brain Barrier in the Pathogenesis of Alzheimers Disease
Rashid Deane and Berislav V. Zlokovic
Affiliation: University of Rochester Medical Center, 601 Elmwood Avenue, Box 670, Rochester, New York 14642,USA.
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
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