Clearance of Amyloid-β Peptide Across the Blood-Brain Barrier: Implication for Therapies in Alzheimer's Disease

The main receptors for amyloid-beta peptide (A beta) 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 A beta 'sinker' that sequesters some 70 to 90% of plasma A beta peptides. In Alzheimer's disease (AD), the levels of sLRP1 and its capacity to bind A beta are reduced which increases free A beta fraction in plasma. This in turn may increase brain A beta burden through decreased A beta efflux and/or increased A beta influx across the BBB. In A beta immunotherapy, anti-A beta antibody sequestration of plasma A beta enhances the peripheral A beta 'sink action'. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-A beta antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-A beta antibody/A beta 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 A beta burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of A beta 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 A. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral A beta 'sink' action, hold potential to reduce brain A beta and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.