Epitope-dependent effects of Beta-amyloid antibodies on Beta-amyloid clearance in an in vitro model of the blood-brain barrier.

To investigate the role of RAGE in the epitope-dependent effects of Aβ antibodies used as a peripheral sink therapy in AD. An in vitro model of the BBB was used to examine the effect of various Aβ antibodies or Aβ peptide fragments on Aβ exchange across the BBB. An N-terminal Aβ antibody significantly enhanced the basolateral-to-apical transcytosis of fluorescein-Aβ(1-42) across the BBB model (41%), while no effect was apparent with a C-terminal Aβ antibody. Interestingly, modulation of RAGE in the presence of a C-terminal Aβ antibody resulted in a 65% increase in Aβ clearance across the BBB model, suggesting the C-terminal antibody-Aβ complex is susceptible to RAGE transport. Additionally, N-terminal peptide fragments of Aβ attenuated the brain penetration of full length Aβ in the BBB model, indicating the N-terminal region of Aβ is required for brain uptake. Antibodies masking the N-terminal region of Aβ increase Aβ clearance across the BBB by preventing Aβ from interacting with the RAGE transporter, whereas antibodies bound to the C-terminus of Aβ are taken up by RAGE and, hence, do not influence the BBB clearance of Aβ.

Bachmeier CJ ，Beaulieu-Abdelahad D ，Mullan MJ ，Paris D ... -  《-》

A multifaceted role for apoE in the clearance of beta-amyloid across the blood-brain barrier.

While apolipoprotein E4 (apoE4) is highly correlated with the development of Alzheimer's disease (AD), its role in AD pathology and, in particular, beta-amyloid (Aβ) removal from the brain, is not clearly defined. To elucidate the influence of apoE on the clearance of Aβ across the blood-brain barrier (BBB). Aβ(1-42) was intracerebrally administered to transgenic mice expressing human apoE isoforms and examined in the periphery. apoE3 and apoE4 mice had 5 times and 2 times, respectively, more Aβ(1-42) appearing in the plasma than wild-type or apoE knockout mice, indicating an enhanced clearance of Aβ from the brain to the periphery. In vitro, unbound basolateral apoE3 (i.e., not bound to Aβ), and to a lesser extent unbound apoE4, at concentrations ≤10 nM facilitated basolateral-to-apical fluorescein-Aβ(1-42) transcytosis across a BBB model, while apoE isoforms bound to Aβ significantly disrupted Aβ transcytosis. Additionally, following apical exposure to the BBB model, we found that apoE4 bound to Aβ is able to penetrate the BBB more readily than apoE3 bound to Aβ and does so via the RAGE (receptor for advanced glycation end products) transporter. These studies indicate a multifaceted, isoform-dependent role for apoE in the exchange of Aβ across the BBB and may partially explain the association of apoE4 and Aβ brain accumulation in AD.

Bachmeier C ，Paris D ，Beaulieu-Abdelahad D ，Mouzon B ，Mullan M ，Crawford F ... -  《-》

Apical-to-basolateral transport of amyloid-β peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein.

Candela P ，Gosselet F ，Saint-Pol J ，Sevin E ，Boucau MC ，Boulanger E ，Cecchelli R ，Fenart L ... -  《-》

Two β-strands of RAGE participate in the recognition and transport of amyloid-β peptide across the blood brain barrier.

Amyloid-β (Aβ) peptide is central to the development of brain pathology in Alzheimer disease (AD) patients. Association with receptors for advanced glycation end-products (RAGE) enables the transport of Aβ peptide from circulating blood to human brain, and also causes the activation of the NF-κB signaling pathway. Here we show that two β-strands of RAGE participate in the interaction with Aβ peptide. Serial deletion analysis of the RAGE V domain indicates that the third and eighth β-strands are required for interaction with Aβ peptide. Site-directed mutagenesis of amino acids located in the third and eighth β-strands abolish the interaction of RAGE with Aβ peptide. Wild-type RAGE activates the NF-κB signaling pathway in response to Aβ peptide treatment, while a RAGE mutant defective in Aβ binding does not. Furthermore, use of peptide for the third β-strand or a RAGE monoclonal antibody that targets the RAGE-Aβ interaction interface inhibited transport of the Aβ peptide across the blood brain barrier in a mice model. These results provide information crucial to the development of RAGE-derived therapeutic reagents for Alzheimer disease.

Kim SJ ，Ahn JW ，Kim H ，Ha HJ ，Lee SW ，Kim HK ，Lee S ，Hong HS ，Kim YH ，Choi CY ... -  《-》

Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier.

Increasing evidence suggests that the soluble form of the β-amyloid peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease. Previously, we reported that treatment with certain antihypertensive dihydropyridine (DHP) compounds can mitigate Aβ production in whole cells and reduce brain Aβ burden in a mouse model of Alzheimer's disease. As Aβ clearance across the blood-brain barrier (BBB) is a key regulatory step in the deposition of Aβ in the brain, we examined the effect of DHP treatment on Aβ brain clearance. Treatment with certain DHP compounds significantly increased Aβ(1-42) transcytosis across the BBB in an in vitro model. The rank order of these compounds was nitrendipine>nicardipine=cilnidipine=lercanidipine>nimodipine>azelnidipine=nilvadipine. Conversely, amlodipine, felodipine, isradipine, and nifedipine had no effect on Aβ(1-42) BBB transcytosis. In an in vivo paradigm of Aβ clearance across the BBB, peripheral administration of nitrendipine, cilnidipine, and nilvadipine to wild-type animals facilitated the brain clearance of centrally administered exogenous Aβ(1-42), whereas with amlodipine, there was no effect. We also observed improved cognitive function in mice treated with nilvadipine following central Aβ(1-42) insult. Thus, in addition to the effect of certain DHP compounds on Aβ production, we demonstrate that certain DHP compounds also facilitate the clearance of Aβ across the BBB. This dual mechanism of action may be particularly effective in attenuating Aβ brain burden in Alzheimer's disease and could open the door to a new class of therapies for the treatment of this disease.

Bachmeier C ，Beaulieu-Abdelahad D ，Mullan M ，Paris D ... -  《-》