Stroke. 2004;35:2628-2631
Published online before print September 30, 2004,
doi: 10.1161/01.STR.0000143452.85382.d1
(Stroke. 2004;35:2628.)
© 2004 American Heart Association, Inc.
RAGE (Yin) Versus LRP (Yang) Balance Regulates Alzheimer Amyloid ß-Peptide Clearance Through Transport Across the Blood–Brain Barrier
Rashid Deane, PhD;
Zhenhua Wu
Berislav V. Zlokovic, MD PhD
From the Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research, Department of Neurological Surgery and Division of Neurovascular Biology, University of Rochester Medical Center, Rochester, NY.
Correspondence to Dr Berislav V Zlokovic, Arthur Kornberg Medical Research Building, University of Rochester Medical Center, 601 Elmwood Avenue, Box 645, Rochester, NY 14642. E-mail berislav_zlokovic{at}urmc.rochester.edu
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Abstract
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Accumulation of amyloid ß-peptide (Aß) in
the central nervous system (CNS) may initiate pathogenic cascades
mediating neurovascular and neuronal dysfunctions associated
with the development of cerebral ß-amyloidosis and
cognitive decline in patients with Alzheimer disease (AD) and
with related familial cerebrovascular disorders. Whether Aß-related
pathology in the CNS is reversible or not and what key therapeutic
targets are controlling Aß/amyloid levels in the aging
brain remain debatable. In this article, we summarize recent
evidence why the receptor for advanced glycation end products
and low-density lipoprotein receptor related protein 1 in the
vascular CNS barriers are critical for regulation of Aß
homeostasis in the CNS and how altered activities in these 2
receptors at the blood-brain barrier may contribute to the CNS
Aß accumulation resulting in neuroinflammation, disconnect
between the cerebral blood flow and metabolism, altered synaptic
transmission, neuronal injury, and amyloid deposition into parenchymal
and neurovascular lesions. We briefly discuss the potential
of advanced glycation end products and low-density lipoprotein
receptor related protein 1–based therapeutic strategies
to control brain Aß in animal models of AD and ultimately
in patients with AD and related familial cerebrovascular ß-amyloidoses.
Key Words: acute care • Alzheimer disease • amyloid ß-protein • blood–brain barrier
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Introduction
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Continuous removal of amyloid ß-peptide (Aß)
species from the central nervous system (CNS) is important for
preventing their potentially neurotoxic accumulations in brain
interstitial fluid (ISF). At the critical threshold concentrations
in brain ISF, Aß may initiate differential pathogenic
cascades mediating neurovascular and neuronal stress and ultimately
the development of cerebral and neurovascular ß-amyloidosis
and dementia in patients with Alzheimer disease (AD) and related
Aß-disorders. Aß is produced by almost all
cells in peripheral tissues and by all types of cells in the
CNS, but Aß’s physiological functions still
remain unknown.
There is little evidence that normal brain aging results in local overexpression of the Aß precursor protein (APP) and overproduction of Aß.1 A relatively small number of AD patients may have increased Aß production in the CNS because of inherited mutations in the APP gene nearby the Aß coding region (ie, Swedish mutation) or presenilins 1 or 2 genes.2 However, the majority of patients with so-called nongenetic or late-onset AD and patients with familial forms of cerebrovascular ß-amyloidoses do not have increased Aß production or APP overexpression in the CNS. These patients likely exhibit a failure in Aß clearance from the CNS because of either deficient transport efflux mechanisms for Aß at the blood-brain barrier (BBB)3,4 or its faulty degradation in the CNS.5 Alternatively, an increased influx of circulating Aß across the BBB may result in Aß brain accumulation or its deposition in the CNS.3,4,6
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Regulation of Aß levels in Brain ISF
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Normal Aß concentrations in brain ISF are carefully
maintained by numerous pathways including (1) Aß production
in peripheral tissues, its systemic clearance and production
in the CNS; (2) rapid receptor-mediated transport exchanges
of free unbound Aß between brain and blood and across
the BBB;
7,8,9 (3) the ability of Aß carrier proteins
(eg, apolipoprotein E [apoE], apoJ,
2-macroglobulin, transthyretin,
and albumin) to bind and sequester Aß in different
extracellular fluid compartments, including plasma, brain ISF,
and cerebrospinal fluid (CSF), or to influence its transport
across the biological membranes isolating these compartments,
including the BBB;
3,7,10,11 (4) Aß degradation by
a variety of proteases, including enkephalinase,
12 insulinase,
plasmin, tissue plasminogen activator, or matrix metalloproteinases;
5 (5) continuous slow removal of Aß through the ISF-CSF
bulk flow into the bloodstream;
13 and (6) oligomerization
2 and
aggregation
14 of Aß in the CNS.
Increased Aß42 levels in brain ISF result in formation of neurotoxic Aß oligomers and progressive synaptic, neuritic, and neuronal dysfunction.2 Alternatively, Aß may form neurovascular or cerebral amyloid aggregates.14 In particular, missense mutations inside the Aß sequence associate with vascular deposits and cerebral amyloid angiopathy.14 The development of cerebral amyloid angiopathy and parenchymal amyloid lesions in AD models is further substantially influenced by apoE and apoJ genes.15
Studies in AD models suggested that Aß brain efflux measurements may be useful for quantifying brain amyloid burden in patients at risk for or those who have been diagnosed with AD.8 For example, the intravenous administration of m266 monoclonal anti-Aß antibody results in rapid efflux of Aß from the CNS into plasma of plate-derived growth factor-driven mice increasing plasma Aß to low nanomolar levels within 24 hours.8 The development of plaques in these mice16 and in senescent nonhuman primate models of cerebrovascular17 and parenchymal ß-amyloidosis18 may shift the Aß transport exchanges between the CNS and its peripheral pool toward the brain.
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Peripheral Aß Pool
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Circulating Aß pool reflects Aß contributions
from peripheral tissues and organs, on the one hand, and the
CNS, on the other. Although the concentrations of free Aß
in brain ISF are
6-fold higher than in plasma under physiological
conditions,
19,20 the absolute amounts of free Aß
in body fluids available for transport exchanges at the BBB
are
10-fold greater than the absolute amounts of Aß
in the brain ISF and CSF.
Increased levels of free Aß in plasma have been reported in AD mouse models21 or after treatment with Aß-peripheral binding agents.8,9,22,23 In AD patients, plasma Aß levels are elevated and mainly incorporated into lipoproteins and different plasma proteins.24,25 The levels of circulating Aß42 and Aß40, after acid denaturation and chromatographic separation of Aß carrier proteins in AD, are 54 nmol/L and 8.6 nmol/L, respectively,25 whereas free Aß in the peripheral venous blood represents only a minute fraction of total plasma Aß (ie, between 60 and 120 pmol/L).19
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Aß Transport at the BBB is Dominated by Receptor for Advanced End Glycation Products and Low-Density Lipoprotein Receptor Related Protein 1
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The BBB in vivo does not allow free exchanges of polar solutes
such as Aß between brain and blood, or between blood
and brain, because of the presence of a continuous monolayer
of brain endothelial cells that are zipped by tight junctions
which effectively isolate brain ISF-CSF compartments from the
plasma compartment.
26 Therefore, specialized receptors at the
BBB must exist to shuttle Aß across the brain endothelium
from CNS into the bloodstream or from blood into the CNS. The
receptor for advanced end glycation products (RAGE) and low-density
lipoprotein receptor related protein 1 (LRP) remain the most
interesting targets, as demonstrated by their ability to rapidly
transport circulating free Aß into the CNS
9 and brain-derived
Aß into the blood,
7,30 (
Figure 1).
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Figure 1. Brain ISF Aß concentrations are regulated by rapid RAGE and LRP-mediated transport at the BBB. RAGE-mediated influx and LRP-mediated efflux for Aß across the BBB were based on kinetic modeling with Aß40 in mice.7,9 Normal brain ISF Aß levels derived from direct ISF measurements in mice,15,20 whereas the CSF levels in AD patients19 and the ISF levels in mouse AD models15,20 were used to approximate brain ISF Aß levels in AD assuming the CSF and ISF concentrations are comparable. Normal plasma concentrations of free Aß in nondemented patients (0.05 to 0.12 nmol/L) derived from several studies.19 The reported plasma levels for Aß40 and Aß42, after acid denaturation and chromatographic separation of plasma proteins in AD patients, were 54 nmol/L and 8.6 nmol/L, respectively.25
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Based on transport modeling with Aß40,7,9 one can calculate that in healthy brain, if influx shut down, LRP efflux could remove all soluble Aß at physiological levels from brain ISF in 1 minute (Figure 1). On the other hand, if efflux shut down, RAGE influx could replace all soluble Aß in brain ISF by plasma Aß in 40 minutes. The high excess capacity demonstrated in the LRP efflux system casts general doubt on theories of increased brain production of Aß as the genesis of late-onset AD.
The possible implications for AD can also be seen from similar transport calculations. For example, if influx shut down, LRP efflux (assuming it remains normal) will be able to remove all soluble Aß from brain ISF at increased levels as seen in AD at 12 nmol/L19 in 40 minutes. If one speculates that all insoluble Aß at pathological levels in the brain could be resolubilized, then based on the transport modeling with Aß40, it would take 65 hours to remove 4 µmol/L per kilogram of resolubilized Aß (Figure 1). On the other hand, if efflux shut down, RAGE influx (if not blocked) could at 2 nmol/L Aß plasma levels replace all soluble Aß in brain ISF (Alzheimer levels) in <2 hours and may create an increment in Aß levels in brain ISF at a rate of 0.15 µmol/L per kilogram per day.
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RAGE/Aß Interactions at the BBB
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RAGE is a multiligand receptor in the immunoglobulin (IgG) superfamily,
which binds soluble Aß and mediates pathophysiologically
relevant cellular responses consequent to ligation by a variety
of ligands.
27 RAGE is implicated in development of Alzheimer
neurovascular disorder by mediating Aß transcytosis
across the BBB,
9,29 by inflammatory and procoagulant responses
in endothelium,
9,27 and by promoting apoptosis through nuclear
factor
B-dependent mechanism,
28 as shown in
Figure 2. Our recent
study has demonstrated that RAGE mediates transport of pathophysiologically
relevant concentrations of Aß into the CNS.
9 After
BBB transport, circulating Aß is rapidly taken up
by neurons inducing cellular stress, whereas RAGE/Aß
interaction in brain endothelium results in elaboration of endothelin-1,
a potent vasoconstrictor, and in suppression of the blood flow.
9
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LRP/Aß Interactions at the BBB
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LRP is a multiligand lipoprotein receptor which interacts with
a broad range of secreted proteins and resident cell surface
molecules (eg, apoE,
2M, tissue plasminogen activator, plasminogen
activator inhibitor-1, APP, factor VIII, and lactoferrin), mediating
their endocytosis or activating signaling pathways through multiple
cytosolic adaptor and scaffold proteins.
30 LRP has been linked
to AD genetically
31 and may influence APP processing and metabolism
and Aß uptake by neurons through
2M.
32 Because APP
mice overexpressing functional LRP minireceptors in neurons
have increased levels of soluble Aß in the brain,
33 it is unlikely that LRP on neurons in vivo mediates Aß
clearance.
Recent studies indicate that LRP is expressed in brain capillary endothelium,7,34 and that LRP along the brain capillary membranes in vivo clears Aß40 into the blood.7 Because the formation of Aß complexes with either apoE or 2M has not been shown in the CNS in vivo during rapid clearance transport studies,7 it is possible that LRP interacts directly with Aß, and that this interaction may result in rapid clearance of Aß on brain capillaries.35
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RAGE and LRP-Based Aß-Lowering Strategies
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Drugs that downregulate RAGE and upregulate LRP at the BBB may
have a capability to readjust the transport equilibrium for
Aß by promoting its efflux from brain into the bloodstream.
In AD and in APP transgenic models of AD, RAGE is significantly
upregulated at the BBB,
7,29 whereas LRP is downregulated.
7 Whether
overexpression of RAGE influences the expression of LRP is currently
unknown. Our recent findings demonstrate that RAGE-specific
IgG can increase the expression of LRP in human brain endothelial
cells exposed to Aß-rich environment by blocking the
effect of Aß on RAGE receptor, suggesting the activities
of the 2 receptors may be linked (
Figure 3A). On the other hand,
drugs that may upregulate LRP by acting directly on BBB endothelial
cells, as we illustrate for the 2 statins (ie, simvastatin and
lovastatin;
Figure 3B and 3C), may also help in clearing Aß
from brain.
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Figure 3. Regulation of LRP expression by RAGE blockade and statins. A, Human brain endothelial cells were incubated in RPMI1640 medium (GIBCO/BRL, New York, NY) containing 0.1% fetal bovine serum and 10 µmol/L Aß42 for 48 hours with and without RAGE-specific IgG (Fab2, 25 µg/mL).9 The levels of LRP (LRP85, light chain) were detected in protein cell lysates by Western blot analysis using human LRP-specific IgG (5A6: 1:350, 5 µg/mL, EMD Biosciences Inc, San Diego, Calif). B and C, Effects of simvastatin (5 µmol/L, Sigma Chemical) and lovastatin (5 µmol/L, Sigma Chemical) on LRP expression by Western blot analysis (conditions as in A.) Scanning densitometry from 3 experiments in A through C (mean±SEM); *P<0.05; **P<0.01 by Student t test.
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The high binding affinity of Aß to RAGE and LRP may offer a basis for development of soluble products that can act as peripheral or central binding agents for Aß. An example of this is sRAGE, a truncated form of the RAGE receptor that does not contain the cytoplasmic domain of the receptor but does contain the V-type binding domain and is able to significantly reduce development of cerebral ß-amyloidosis in an AD mouse model.9 Another example could be soluble LRP fragments that bind directly Aß.26 Thus, future preclinical studies in APP animal models of AD should show whether RAGE and LRP-based strategies to modify Aß transport exchanges at the BBB will have a major impact on clearing Aß/amyloid across the BBB, with an ultimate goal to provide a safe therapy to control cognitive decline in AD and related cerebrovascular disorders.
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Acknowledgments
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This research was supported by grants from the US Public Health
Service AG16223, NS34467, and AG23084 to B.V.Z.
Received July 12, 2004;
accepted August 5, 2004.
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Abstract
Introduction