Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease.
The main receptors for amyloid-beta peptide (Abeta) transport across the blood-brain barrier (BBB) from brain to blood and blood to brain are low-density lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE), respectively. In normal human plasma a soluble form of LRP1 (sLRP1) is a major endogenous brain Abeta 'sinker' that sequesters some 70 to 90 % of plasma Abeta peptides. In Alzheimer's disease (AD), the levels of sLRP1 and its capacity to bind Abeta are reduced which increases free Abeta fraction in plasma. This in turn may increase brain Abeta burden through decreased Abeta efflux and/or increased Abeta influx across the BBB. In Abeta immunotherapy, anti-Abeta antibody sequestration of plasma Abeta enhances the peripheral Abeta 'sink action'. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Abeta antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Abeta antibody/Abeta immune complexes are rapidly cleared from brain to blood via FcRn (neonatal Fc receptor) across the BBB. In a mouse model of AD, restoring plasma sLRP1 with recombinant LRP-IV cluster reduces brain Abeta burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Abeta is required for its direct interaction with sLRP and LRP-IV cluster which is completely blocked by the receptor-associated protein (RAP) that does not directly bind Abeta. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Abeta 'sink' action, hold potential to reduce brain Abeta and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.
Deane
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Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. Rashid_Deane@urmc.rochester.edu
Bell
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Sagare
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Zlokovic
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D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011961:Receptors, Fc / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000906:Antibodies; D015395:Histocompatibility Antigens Class I; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000067759:Receptor for Advanced Glycation End Products; D011961:Receptors, Fc; D011971:Receptors, Immunologic; C100688:Fc receptor, neonatal