Clearance of Amyloid-β Peptide Across the Blood-Brain Barrier: Implication for Therapies in Alzheimers Disease
R. Deane, R. D. Bell, A. Sagare and B. V. Zlokovic
Pages 16-30 (15)
The main receptors for amyloid-beta peptide (Aβ) 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 Aβ ‘sinker’ that sequesters some 70 to 90 % of plasma Aβ peptides. In Alzheimers disease (AD), the levels of sLRP1 and its capacity to bind Aβ are reduced which increases free Aβ fraction in plasma. This in turn may increase brain Aβ burden through decreased Aβ efflux and/or increased Aβ influx across the BBB. In Aβ immunotherapy, anti-Aβ antibody sequestration of plasma Aβ enhances the peripheral Aβ ‘sink action’. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Aβ antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Aβ antibody/ Aβ 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 Aβ burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Aβ 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 Aβ. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Aβ ‘sink’ action, hold potential to reduce brain Aβ and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.
Amyloid-β Peptide, Blood-Brain Barrier, Alzheimer's Disease, lipoprotein receptor, immunotherapy
Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.