Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease - PubMed (original) (raw)
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Clearance of amyloid-beta peptide across the blood-brain barrier: implication for therapies in Alzheimer's disease
R Deane et al. CNS Neurol Disord Drug Targets. 2009 Mar.
Abstract
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.
Figures
Figure 1. Schematic diagram showing the blood and brain compartments, and the roles of the cell surface receptors LRP1 and RAGE, and FcRn and soluble LRP (sLRP) in the regulation of Aβ transport across the blood-brain barrier (BBB)
See text for details. RAGE (receptor for advanced glycation end products), LRP1 (low-density lipoprotein receptor related protein 1), FcRn (neonatal fragment crystalline (Fc) receptor) and TJ (tight junctions between cerebrovascular endothelial cells).
Figure 2. Aβ binds to human plasma derived sLRP and human recombinant LRP-IV cluster but not to RAP using ELISA
Briefly, 10 μg/ml human sLRP, recombinant LRP-IV or RAP were coated on microtiter plates and blocked with protein-free blocking buffer (Pierce 37570). For sLRP and LRP-IV, 100 nM Aβ40 was added and incubated in HBSC, pH 7.4, for 2 hours at room temperature. For RAP, various Aβ40 concentrations (0, 1, 40, 1 and 100 nM) were used. After washing with HBSC containing 0.05% Tween-20, the N-terminal specific (Cell Signaling Cat # 2454, 1μg/ml) or C-terminal specific (BA27, WAKO ELISA kit) primary antibodies were added and incubated overnight. The secondary antibody for the N-terminal anti-Aβ antibody was goat anti-rabbit (Dako; 1:2000), while the C-terminal specific primary antibody was already HRP-conjugated. The reaction was developed with 3,3′5,5′ tetramethlbenzidine (TMB; KPL,Gaithersburg, MD) and stopped with 1M HCl. Absorbance was read at 450 nm. Aβ bound to immobilized human plasma derived sLRP (A) or immobilized recombinant human LRP-IV cluster (B) in the absence or presence of RAP (1 μM) was detected using an N-terminal specific (white bars) or a C-terminal specific (black bar) anti-Aβ antibody (αAβ). C, No significant binding of monomeric Aβ40 to RAP was detected using the N-terminal specific anti-Aβ antibody. In A-C, values are mean + standard error of the mean, n=3 for each group. Pairs of groups were statistically analyzed using students t-test. These are previously unpublished data from the Zlokovic laboratory.
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