Berislav Zlokovic led this live discussion on 23 June 2003. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
Berislav Zlokovic, University of Rochester, led this live discussion on 23 June 2003.
Participants: Kim Green; Ladislav Volicer, Boston University Medical School; Berislav Zlokovic, University of Rochester Medical Center, New York; Martha E, Stokely University of North Texas Health Sciences Center; Dave Holtzman, Washington University, St. Louis, Missouri; Alexei Koudinov, Peoples Friendship University of Russia, Moscow; Anne Fagan, Washington University in St. Louis; Yasuji Matsuoka, New York University School of Medicine; Jorge Busciglio, University of Connecticut Health Center; Rolf W, Warzok University of Greifswald, Bonn, Germany; Tadafumi Hashimoto, University of Tokyo; Andrea, Case Western Reserve University; Leigh Holcomb, Texas A&M Neuropsychiatry Research Program; Gaku Sakaguchi, Nathan Kline Institute; Dietmar Thal, University of Bonn Medical Center, Germany; Atul Deshpande, University of Connecticut Health Center; Michal Schnaider, Beeri Psychiatry Department at Mount Sinai School of Medicine.
Note: The transcript has been edited for clarity and accuracy.
Hi, and welcome everyone. I am Gabrielle Strobel, managing editor of Alzforum, and pleased to moderate today. While people are still arriving, perhaps Berislav could start with a question growing right out of his Nature Medicine paper. Many people probably wonder if soluble Receptor for Advanced Glycation End-products (sRAGE) could be a potential therapy, Berislav?
In principle, Ab-binding agents could be, and sRAGE is part of that group. So the answer is yes.
Berislav, is it known where sRAGE is metabolized systemically after it is injected?
The pharmacokinetic studies are in progress; it is likely to be excreted by the kidney and perhaps liver.
Are there any compounds with an affinity to the physiological form of Ab that could be sequesterers?
The higher the affinity, the better.
Berislav, any Ab deposition in peripheral organs after treatment?
Not observed, but we did not look hard enough into it.
Perhaps we could address the first question in the backgrounder: What should the next experiments be to advance this potential therapeutic approach?
Perhaps to look into high affinity Ab peripheral binding agents that could also reduce inflammation and improve cerebral blood flow (CBF). Possibly further chemical design of the sRAGE molecule to optimize its binding to Ab, and producing smaller molecules, such as V-domains.
As RAGE is transporting Ab into the brain, would this suggest that Ab is being produced in the periphery?
Ab can be produced in the periphery, but also during processes that dissolve amyloid plaques from the brain, so a bulk may come from the CNS.
So you would surmise that increased cerebral AbP leads to decreased CBF?
Yes, increased Ab decreased CBF. After treatment with sRAGE, the levels go up from normal 50-100 pmol/L to about 1.5 nmol/L, about a 20-fold increase.
Interesting, as I would guess that a decrease in CBF would cause an increase of AbP!
Kim, what exactly is AbP?
Amyloid b peptide production.
We did not look into it; I was referring to Ab levels.
Berislav, add (with regard to the possibility of the systemic production of Ab) that we showed some years ago that Ab is produced in HepG2 hepatocytes (Cell Biol Inter, 1997).
How far along are experiments to determine whether RAGE KO x APP transgenic mice exhibit changes in Ab deposition/Ab metabolism?
Some of it has been completed, but only in the earlier age group, five to six months, I believe. They do much better on behavioral tasks and develop less Ab. More conclusive studies are in progress with older age groups.
Berislav, what APP mice did you cross with?
With RAGE KO. This work has been done with Shid Du Yan and Mark Kindy. The APP was PD-hAPP.
Berislav, did you do your sRAGE treatments in different mouse models that varied in terms of how much cerebral amyloid angiopathy (CAA) they had? I wonder what your data reveal about CAA.
Detailed studies are in progress. In terms of CAA, we showed that sRAGE treatment increases blood flow.
Berislav, any notable amount of peripheral Ab in PDAPP?
Berislav, I have a basic question: Is RAGE a receptor for the monomeric, oligomeric or fibrillar form of Ab?
According to literature, it can bind both fibrillar and monomeric forms.
Berislav, while it seems likely from your paper that the effect on Ab deposition of chronic sRAGE treatment of APP mice over three months is due to a peripheral effect, can you rule out a central effect of the small percentage of sRAGE that crosses into the CNS?
While Berislav is answering some questions put to him, I was wondering if Yasuji could tell us about ongoing work with small molecules that bind Ab in the periphery. Anything you could tell following your paper on gelsolin?
We are testing other classes of Ab binding agents because chemical modification of gelsolin and GM1 is not realistic. I found a few Ab binding agents that could alter both brain and plasma Ab.
All: Do receptor-mediated transport mechanisms respond in the same way to peripheral sequestration as passive flow would, i.e., will CNS levels go down if Ab is removed from the peripheral pool?
I think that capturing Ab in the periphery will lower the total amount of Ab from the peripheral pool available for exchange with its central pool; this might move Ab from brain to periphery.
Dr. Zlokovic should be an expert in this subject with his pioneering earlier papers on receptor-mediated Ab transport. I mean receptors related to lipoprotein (LP) transport.
Alexei, we believe that LRP-1 is important in elimination from brain.
Berislav, is LRP-1 the only one?
...and this Q points to a pre-discussion background point on AD as a systemic disease. If so, the change in the systemic pool of Ab should affect the CNS levels.
We found that LRP-1 clusters II and IV bind Ab and its mutants with high affinity. It is probably a major efflux mechanism at the BBB. There may be some other mechanisms, depending on which form Ab is in.
Dr. Zlokovic, what do you think is the role of astrocytes in regulating Ab homoeostasis in the neuropil, especially in regard to their function in the blood brain barrier?
Dietmar, I am not sure that the regulatory role of astrocytes in Ab BBB transport is well-understood at this time. Very interesting possibility. Perhaps Dave can make some comments regarding GFAP-ApoE mice.
I think it is likely that ApoE regulates BBB transport of Ab. ApoE is made in astrocytes. Whether astrocytes play a role outside of ApoE and also ApoJ production, I don't think anyone knows.
Rolf Warzok has worked on the p-glycoprotein (known as the transporter that pumps drugs out of tumor cells), suggesting it may transport Ab out of endothelial cells, as well. Do we know anything about its role vs. LRP? Berislav, all?
Rolf W. Warzok
In our studies we found an inverse correlation between P-glycoprotein and Ab load. Subjects with ApoEE4 had lowest PGP levels.
Does LRP-1 have a sensor machinery for decreasing amyloid in the periphery?
Hi, Gaku; yes, it has high affinity to bind Ab in periphery as well, and soluble fragments may act as binding agents.
In regard to Ab in the blood, if it is bound to a large molecule, that should prevent it from reentering the brain unless the large molecule is actively transported into brain. If there are transport systems that "sense" Ab levels in the periphery and somehow respond to that in some way, it is not known, I believe.
I agree with Dave.
Again, while Berislav is busy replying, can I ask Dave and Yasuji one of the questions in the background text? Is serum Ab truly out of the picture once it is bound? Could transport systems "sense" that bound serum Ab is increasing, and reduce Ab efflux in response? If so, peripheral sequestration could lead to an unintended increase of CNS Ab. Have animal models ruled this out? Or is there an error in the thought?
Plasma Ab levels returned to the baseline quickly after treatment with simple Ab binding agents, such as gelsolin, GM1 and new testing compounds. Ab disappeared from the blood in the case of simple Ab binding agents. We are working out the pathway.
Recently there was an article suggesting that astrocytes internalize Ab. Would that be of any significance in decreasing the Ab load in the brain and transporting it across the BBB into the blood? (See ARF related news story).
It would seem that astrocytes have the potential to play a major role in Ab metabolism, since they express many receptors for molecules that bind Ab.
Dave, that's what I meant by saying earlier that Ab transport regulation is a systemic event, the sensing machinery of transport.
Alexei, I agree with you that it could be a "systemic" event.
If astrocytes can resolubilize amyloid and release free Ab, in the presence of a stable efflux system at the BBB, this can be a possibility. I am not aware, however, of any study that has tested this possibility in an animal model.
Another question for all from the background text: Are there ways of stimulating peripheral degradation of Ab in the liver and the kidney? That would take it out of the equation faster, too.
Yes, I totally agree—same as dialysis.
What is the role of ApoE in regard to the drainage of Ab from the brain to the vessels? Do you have an explanation for our finding that capillary Ab deposition is strongly associated to the ApoE4 allele?
Dietmar, what is your explanation for this event?
We are studying details now. In our earlier work (J Neurochem, 1997), we showed that ApoE2 and 3 prevent Ab transport across the BBB, while ApoE4-bound Ab can get into the brain from periphery.
Alexei, our attempt to explain this finding is that Ab-ApoE complexes are less soluble when E4 is present.
It is very interesting that one of the major effects of ApoE on Ab is on CAA (even more than on parenchymal plaques). Perhaps drainage of Ab from brain and/or via the BBB is influenced by the transport/drainage of ApoE out of brain via receptors/heparin sulfate proteoglycans (HSPGs) and others.
Dave, I agree; this is an interesting possibility. It could also be related, though, to the level of LRP-1 expression at the BBB.
Could you explain how HSPG would be involved?
HSPGs are concentrated near vessels, and ApoE binds strongly to HSPG. I agree LRP-1 may also help co-localize ApoE at the BBB.
This is also a possibility, as ApoE binds to clusters II and IV as well as Ab.
Berislav, for the non-expert: What are clusters II and IV?
These are soluble forms of LRP-1 receptors part II and IV. (There is VI + cytoplasmic tail.)
Dietmar, I remember that we discussed while referring to and discussing papers by Berislav that there could be a competition for Ab and ApoE (E2-, 3-, 4-specific) for binding to LPR.
Are there any other pathological alterations in blood vessels, besides CAA, that could be responsible for lowering Ab resorption?
Yes, this includes senescence of the vascular system (replicative or stress-induced) and aberrant angiogenesis in response to VEGF and bFGF.
Berislav, Yasuji, Dave, others, are you trying to find and develop lead compounds on your own, or have companies licensed the drug development piece? I am asking because Alzforum is thinking about what sorts of information resources we could help establish for academic scientists who are pursuing their treatment hypothesis themselves, at least part of the way, to create more validated drug leads. What sorts of information can be hard to find that we could help assemble? Contacts and names of contract research organizations (CROs) who do toxicology and pharmacokinetic studies? Places to purchase compound libraries? Any needs we should think about?
Gabrielle, yes, I am trying.
Rolf W. Warzok
Dietmar, vessels with high Ab have low PGP and vice versa. We never registered a coexpression of Ab and PGP in the same vessels. In other words, only in vessels with no PGP was Ab observed in double staining immunohistochemistry.
Interesting; so you suspect PGP to be a major exporter? How about LRP? Did you assess that?
If PGP is a major exporter, wouldn't you expect PGP KO mice to have higher levels of Ab in the CNS? Has this been done?
Rolf W. Warzok
So far we haven't looked at LRP. We are just now looking at this in mice.
Rolf, we were not able to observe so reproducibly that ABC transporters are associated with CAA using microarray analysis, but in about 50-60 percent of AD cases we also found downregulation of ABA-1 associated with Tangier's disease, and MRP-1 associated protein. We also reported that reduced expression of LRP-1 is associated with increased levels of vascular Ab. The CAA here may also be secondary to senescence, and Ab accumulation secondary to LRP-1 downregulation that is down in senescent endothelium.
In AD, due to inflammation and activation, the BBB is probably compromised; that could also play a role in the entry of Ab into the brain and vice versa.... Just a thought.
Also, Berislav, do you know the effect of RAGE deficiency on the steady-state endogenous Ab levels in the brain and plasma? Someone asked that in a comment.
It's in works currently with Shi Du Yan from Columbia.
We are nearing the end of the hour. Let me thank Berislav and everyone very much for coming. This looks like a promising line of investigation and we sure hope something comes of it.
By Berislav Zlokovic
In yesterday's online version of Nature Medicine, our lab and colleagues published a report about blocking Ab brain import from the periphery across the blood-brain barrier via the endothelial receptor RAGE. The text below first summarizes the main news in this paper, and then lays out the transport-clearance hypothesis of Ab and related Ab-lowering strategies in more breadth and detail.
Synposis of Deane et al. (15a)
We found that RAGE in brain endothelium mediates transport of circulating unbound (free) Ab across the blood-brain barrier (BBB). At pathophysiological levels, this transport results in neurovascular stress and reductions in cerebral blood flow (CBF). Both a soluble form of RAGE (sRAGE) and RAGE-specific IgG block Ab transport at the BBB and the resulting reductions in CBF in wild-type and Tg2576 mice. Treatment of PD-hAbPP mice with sRAGE reduces amyloid load and Ab levels in the brain. Data suggest that peripheral non-immune scavenging agents such as sRAGE efficiently shift Ab exchanges across the BBB, favoring egress of peptide from brain. Flux calculations indicate that at pathophysiological Ab plasma levels in Tg2576 mice or PD-hAbPP mice treated with an antibody or sRAGE, the Ab plasma pool can still rapidly replenish Ab brain levels at remarkably high rates close to 0.15 micromoles/kg brain interstitial fluid per day. Thus, neutralizing the peripheral pool of Ab and blocking its transport across the BBB should lower the risk of generalized neuroinflammation and of compromise of the blood flow during Ab-lowering therapeutic interventions associated with increases in circulating free Ab.
Ab Transport-Clearance Hypothesis
Increases in Ab production can explain a small percentage of early-onset cases of familial AD in those people who carry inherited mutations in the AbPP gene that flank the Ab coding region (i.e., Swedish mutation) or the presenilin 1 or 2 genes. (27) Increases in production have not, however, been found in sporadic AD, or in familial AD/CAA where people inherited mutations inside the Ab coding region (e.g., Dutch, Iowa); an exception here is the Flemish mutation. Consequently, we could regard b-amyloidosis in sporadic and even some familial AD as a "storage" disease caused by inefficient clearance of a peptide that is normally produced in the CNS. (28,36,37) In general, any mismatch between Ab production, transport of circulating Ab into the CNS and clearance-whether resulting from increased production, increased transport of blood-borne peptide or inadequate clearance-may result in Ab accumulation in the CNS, and the two plausible hypotheses for its clearance from the brain are metabolism (41,42,89) and transport out. (36,37) Here we will discuss Ab transport, and why our current understanding of this process lends support for the therapeutic strategy of the "peripheral sink."
Transport of Ab in the CNS: Part Drifting, Part Shipping
Nonspecific bulk flow of brain interstitial fluid seems to be responsible for about 10-15 percent of Ab clearance from normal brain. (29) The blood-brain-barrier (BBB) normally prohibits free exchange of polar solutes, such as Ab, between brain and blood or blood and brain, mostly because of the presence of tight junctions between brain endothelial cells that form a continuous monolayer. Therefore, carrier-mediated or receptor-mediated transport system(s) for Ab must exist at the BBB to remove Ab from the CNS and inject it into circulation shortly after its physiological production (37), or to shuttle circulating Ab into the CNS. In 1993 we suggested that carrier and/or receptor-mediated transport across the BBB regulates brain Ab (34), and since then numerous reports from different groups have verified this hypothesis. (1-5,8,9,11,16-23,25,26,29,34-37)
1. Brain Export
Recent studies in PDAbPP mice have demonstrated that a single intravenous injection of the m266 monoclonal anti-Ab antibody promotes a rapid outflow of Ab from the CNS into plasma, increasing plasma Ab from baseline levels of 200 pg/ml to 5-10 ng/ml within 24 hours. (3) Given the similarity in plasma and CSF levels of Ab between humans and PDAbPP mice (6), DeMattos et al. suggested that Ab efflux measurements from brain to plasma after challenge with an anti-Ab antibody may be useful for quantifying brain amyloid burden in patients at risk for Alzheimer's, or diagnosed with the disease (see ARF related news story). As plaques develop in primate models of b-amyloidosis and in transgenic mice, soluble Ab from brain and plasma settles onto amyloid deposits in the CNS and around blood vessels and, consequently, the transport equilibrium for Ab between the CNS and plasma shifts (1,3-5,18). Using a squirrel monkey model of cerebral amyloid angiopathy (CAA), our lab recently confirmed that Ab is rapidly eliminated from brain into plasma across the BBB, and we noticed an age-dependent decline in this Ab clearance via the BBB that correlates with increases in amyloid deposition and Ab cerebrovascular immunoreactivity. (1,18)
How Does Ab Get Out? Ask LRP-1
LRP-1 is a large, multifunctional scavenger and signaling receptor belonging to the LDL receptor family. (10) LRP-1 was first discovered as a key endocytic receptor for the transport and metabolism of cholesterol and ApoE-containing lipoproteins. Its 515 kDa heavy chain contains four ligand-binding domains (clusters I-IV) that bind numerous structurally unrelated ligands, including ApoE, a-macroglobulin, tissue plasminogen activator, plasminogen activator inhibitor-1, AbPP, factor VIII, and lactoferrin. The 85 kDa light chain of LRP-1 contains a transmembrane domain and a cytoplasmic tail. The latter can be phosphorylated on serine, which has been linked to enhanced endocytosis, or on tyrosine; see review. (10)
We recently showed that LRP-1 functions as a clearance receptor for Ab at the BBB. (29) The LRP-1-mediated crossing (or transcytosis) of Ab begins at the brain side of the endothelium and is, therefore, directly responsible for eliminating Ab from the brain's interstitial fluid into blood (Fig. 1). It is not understood what the exact molecular mechanisms are that regulate interactions of Ab?with LRP-1 at the BBB, but we do know that the LRP-1 ligands ApoE and a-macroglobulin can influence Ab clearance.
The expression of brain endothelial LRP-1 appears to go down during normal aging in rodents, nonhuman primates, and in AD patients associated with positive staining of vessels for Ab40 and Ab42. (29) There is a genetic association between LRP-1 and the development of AD, but the biochemical mechanisms by which LRP-1 could affect the onset of the disease remain unknown. (10) Our most recent in vitro surface plasmon resonance studies indicate that Ab40 and Ab42, as well as Dutch and Dutch/Iowa mutants of Ab40, are direct ligands for sLRP-1 clusters II and IV; moreover, all Ab peptides bind directly to the abluminal site of the BBB via LRP-1 with high affinity. (38)
2. Brain Import
The autosomal dominant mutations that cause early-onset AD all increase Ab42 in plasma and brain. A late-onset AD locus on chromosome 10 acts to increase plasma Ab. The few studies that have analyzed plasma Ab levels in AD patients vs. age-matched controls suggest either no change or increased levels in AD, and/or an increased risk for AD in cognitively normal elderly individuals with high levels of plasma Ab as reviewed. (6) Tg2576 mice overexpressing AbPP develop high plasma levels of Ab40 and 42 (4 nM and 0.5 nM, respectively), between three and nine months of age. (14) PDAbPP mice have significantly lower baseline values of plasma Ab (~200 pg/ml), but these levels shoot up 40-fold after a single intravenous injection of anti-Ab antibody (3) or sRAGE. (33). Ab circulating at such pathophysiological concentrations can be rapidly transported back into the CNS. (11,15,20,34) Therefore, trapping Ab in plasma is critical to reducing Ab levels in the CNS and to shift the plasma-CNS equilibrium of Ab, at least in these models.
Agents that bind Ab in plasma but do not themselves penetrate the BBB may promote the outflow of a rapidly mobilized, soluble pool of Ab, acting as a peripheral "sink." If such agents do enter the CNS, they may bind soluble brain Ab. This would promote resolubilization of previously aggregated Ab as the brain equilibrium between soluble and aggregated Ab shifts towards the soluble side, and this in turn should result in Ab elimination from the CNS provided the clearance systems are intact.
How Does Ab Get In? Ask RAGE
RAGE is a receptor in the immunoglobulin superfamily. In addition to Ab, it binds a broad repertoire of ligands, including products of nonenzymatic glycoxidation (AGE), the S100/calgranulin family of proinflammatory cytokine-like mediators, and the high-mobility group 1 DNA-binding protein amphoterin. (31) RAGE biology is largely dictated by its ligands in that mature animals show little RAGE expression in most tissues until deposition of ligands triggers expression. When pathogenic Ab species accumulate in AD (32) or transgenic models of b-amyloidosis, RAGE expression increases in affected cerebral vessels, neurons, or microglia. In contrast to the ligand-mediated receptor downregulation observed with LDL receptors in a lipoprotein-rich environment (10), or LRP-1 in an Ab-rich environment (29), RAGE is upregulated by its ligands. This mechanism could exacerbate cellular dysfunction. RAGE binds soluble Ab in the nanomolar range, and then mediates pathophysiologic cellular responses. (31) RAGE is upregulated in the AD brain vasculature (32) and it regulates binding and transport of Ab in a human model of the BBB. (16) In light of these findings, we have recently shown that, in vivo, Ab binding to RAGE at the brain endothelium may increase transport of circulating Ab into the CNS. We also think RAGE is involved in diminishing cerebral blood flow, accompanying amyloid angiopathy, and proinflammatory events as observed in AD brain. In support of this hypothesis, we have found that RAGE mediates transport of physiological and pathophysiological concentrations of plasma Ab across the BBB into the brain, and that the latter leads to expression of proinflammatory cytokines in neurovascular cells and elaboration of endothelin-1, causing decreased cerebral blood flow. (15,15a)
Finally, there is also LRP-2 at the BBB. It may import plasma Ab complexed with apolipoprotein J (ApoJ). (35) Yet LRP-2 is normally saturated by high levels of plasma ApoJ , which precludes significant influx of Ab into the CNS. This leaves RAGE as the major Ab influx receptor at the BBB.
Where does all this leave us? Peripheral Ab-binding agents may well promote clearance of brain-derived Ab, thereby reducing Ab levels and amyloid load in the CNS of different AbPP-overexpressing mice. In the current online Nature Medicine, we have shown that sRAGE completely prevents transport of circulating Ab into the CNS, and since it does not penetrate the CNS in appreciable amounts it may act as a sink, favoring egress of Ab from brain. (15,15a) Moreover treatment with sRAGE improves the blood flow in Tg2576 mice, reduces neuroinflammation caused by pathophysiological levels of plasma Ab, and reduces amyloid load and Ab40/42 levels in PD-hAbPP mice. (15a,33) Serum amyloid P (SAP) component can be removed from human amyloid deposits in peripheral tissues by drugs that are competitive inhibitors of SAP and may enable its rapid clearance (24) (see ARF related news story). It has been also suggested that insulin-like growth factor I may induce clearance of brain Ab, probably by enhancing the import into the CNS of Ab-carrier proteins such as albumin and transthyretin. (2) This therapeutic approach is alive and well, and we will discuss which gaps we must still fill in our basic understanding of Ab transport, which models are best suited to test the therapeutic approach, and whether current experimental compounds are promising.
Thumbnail Summary of Transport-Clearance Hypothesis
Out of the Brain: LRP-1 mediates rapid Ab transcytosis across the BBB. (29) In parallel, the interstitial fluid bulk flow into the CSF slowly removes soluble Ab. Into the Brain: RAGE mediates influx of free, circulating Ab across the BBB into the CNS. (11,15,16) Ab-sequestering agents such as sRAGE (15,33), anti-Ab IgG (3,30), gelsolin and/or GM1 (22), or sLRP-1 clusters II and IV (38) can mop up Ab in plasma, reducing its influx across the BBB. Eliminating contributions of the circulating pool of Ab to its central pool may promote Ab's flow from brain into blood; this could be particularly important in cases of sporadic AD where the efflux transport systems are defective, such as down-regulated LRP-1. (29)
We suggest these questions for discussion:
- What should the next experiments be to advance this potential therapeutic approach?
- Do receptor-mediated transport mechanisms respond in the same way to peripheral sequestration as passive flow would, i.e., will CNS levels go down if Ab is removed from the peripheral pool?
- Is serum Ab truly out of the picture once it is bound? Could transport systems "sense" that bound serum Ab is increasing, and reduce Ab efflux in response? If so, peripheral sequestration could lead to an unintended increase of CNS Ab. Have animal models ruled this out?
- Do peripheral Ab-antibody complexes get degraded faster or slower than Ab alone? Could they pile up and cause problems?
- The m266 work is a promising approach. How far along is it?
- Are there ways of stimulating peripheral degradation of Ab in the liver and the kidney?
- Does the importance of Ab clearance and peripheral degradation make AD a systemic disease?
- Is it desirable to solubilize aggregated Ab? Might soluble intermediates be toxic?
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