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Role of the Low-density Lipoprotein Receptor–Related Protein in -Amyloid Metabolism and Alzheimer Disease

Bradley T. Hyman, MD, PhD; Dudley Strickland, PhD; G. William Rebeck, PhD

Arch Neurol. 2000;57:646-650.

ABSTRACT
Deposition of -amyloid (A), a metabolite of approximately 4 kd of the amyloid precursor protein, is a critical pathological feature in Alzheimer disease. We postulate that deposition reflects an imbalance of A synthesis and clearance. Several pathways that impact A converge on a single receptor molecule, the low-density lipoprotein receptor–related protein (LRP). This multifunctional receptor is the major neuronal receptor both for apolipoprotein E (apoE, protein; APOE, gene) and for ₂-macroglobulin (₂M, protein; A2M, gene), and it mediates clearance of apoE/A and ₂M/A complexes. The LRP also interacts with the amyloid precursor protein itself. In this review, we highlight data that support a role for LRP in A metabolism and hypothesize that LRP therefore plays a critical role in Alzheimer disease.

INTRODUCTION

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The neuropathological characteristics of Alzheimer disease (AD) include the development of neurofibrillary tangles and senile plaques throughout cortical and limbic brain regions, ultimately leading to marked neuronal and synaptic loss and cortical atrophy.^1-2 Senile plaques consist of -amyloid (A), a peptide made up of 40 or 42 amino acids derived from the amyloid precursor protein (APP).³ Early-onset autosomal dominant AD is caused by mutations in APP, presenilin 1, or presenilin 2,^4-6 all of which modify A synthesis,^{3, 7-8} suggesting a central role for A in causing AD.

The early-onset autosomal dominant forms of the disease, in which the key metabolic error is a presumed alteration in A synthesis, are quite rare. We hypothesize that late-onset AD, which accounts for the vast majority of all AD (and indeed of all dementia), may be caused by alterations in A clearance mechanisms. The idea that A clearance occurs at all is based, in part, on the observation that the total amount of A (called the A burden) in AD brains remains fairly constant from early in the disease until the end stage, suggesting a steady state of A deposition and clearance.⁹ Detailed examination of the geometry of A deposits and computer modeling of aggregation and disaggregation models support this idea.^10-11 Moreover, in vitro, several molecular mechanisms for clearance of A or small A aggregates have been demonstrated, including microglial clearance¹² via the macrophage scavenger receptor¹³ or the receptor for advanced glycation end products.¹⁴

Herein, we postulate that a major clearance route for A is by forming complexes with 2 proteins known to bind and clear a variety of molecules: apolipoprotein E (apoE) and ₂-macroglobulin (₂M). Both of these molecules are internalized by a common receptor, the low-density lipoprotein receptor–related protein (LRP). Several lines of evidence suggest that LRP plays a prominent role in putative A clearance pathways and support the hypothesis that LRP occupies a critical position in the complex metabolic cascades that influence the balance of A clearance and synthesis. We first review the LRP structure and known functions and then examine in more detail the evidence implicating 3 different LRP ligands (apoE, ₂M, and APP itself) in the disease process.

STRUCTURE AND FUNCTION OF LRPs

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The LRP is a multifunctional receptor greater than 600 kd (4454 amino acids in length) with a single transmembrane-spanning domain expressed on the cell surface (Figure 1). It is cleaved by furin in the trans-Golgi network to form a heterodimer.¹⁵ The extracellular domain (approximately 515 kd) contains multiple epidermal growth factor and growth factor repeats and 4 distinct ligand binding sites. An 85-kd carboxy terminal domain contains 2 intracellular NPXY sites that direct endocytosis of the receptor.^16-17 In the central nervous system, the LRP is strongly expressed on neurons and is also upregulated on activated astrocytes and microglia, placing it in an ideal location to clear a variety of bioactive substances. The LRP is also found on senile plaques¹⁸ (Figure 2).

View larger version (16K): [in this window] [in a new window] Figure 1. Low-density lipoprotein receptor–related protein (LRP) structure. The multiple repeat regions in the extracellular domain create ligand binding sites, whereas the relatively small intracellular domain contains 2 NPXY sequences important for LRP trafficking.

View larger version (71K): [in this window] [in a new window] Figure 2. Results of immunohistochemical staining for low-density lipoprotein receptor–related protein (antibody R77718) of neurons and senile plaques in an Alzheimer disease brain specimen (original magnification, x160).

The LRP has more than 20 identified ligands, many of them of import in the central nervous system. The ligands fall into several broad categories: apoE and lipid-related ligands; proteinase and proteinase inhibitor complexes (including APP containing Kunitz proteinase inhibitor, ₂M, and tissue plasminogen activator and plasminogen activator inhibitor 1 complexes); and others (eg, lactoferrin). The binding of ligands to LRP leads to endocytosis and degradation, which can be blocked by the receptor-associated protein. The receptor-associated protein is a 39-kd protein that was initially isolated with LRP and has a very high affinity for LRP.¹⁷ Used pharmacologically, the receptor-associated protein blocks binding of all known LRP ligands.^19-21

apoE AND AD

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Apolipoprotein E is a small protein that contains 2 major domains: an amphipathic helical domain that binds to hydrophobic substances, and a receptor binding domain that binds members of the low-density lipoprotein receptor family,²² including LRP.²³ Immunohistochemical results showed that antibodies to apoE stained senile plaques^24-25 when data from genetic studies implicated it in the pathogenesis of AD. The APOE gene is inherited in 3 common alleles ( 2, 3, and 4). Inheritance of the APOE4 allele is a genetic risk factor for late-onset AD (age 60 years or older) both in individuals with a family history of AD²⁶ and in the general population.^{18, 27-29} Heterozygosity for APOE4 increases the risk for AD compared with the common APOE 3/3 genotype by approximately 3-fold; APOE2 decreases the risk for AD by about half, and homozygosity changes the odds ratios to an even greater extent (see Hyman³⁰ for review).

Several hypotheses have been proposed for the role of apoE in AD. It has been implicated in clearance of debris after neuronal injury.^{22, 31} There are isoform-specific effects on neurite outgrowth, mediated through LRP,^32-33 and on in vitro apoE- complex formation.³⁴ Apolipoprotein E also can modulate A fibrillogenesis, although under different conditions apoE4 produces either a promoting or inhibiting effect.^35-38 We postulated that apoE may be involved in an A clearance mechanism.¹⁸ Consistent with this idea, there is a clear effect of the APOE genotype on A deposition. Inheritance of APOE4 is associated with increased deposition of A in plaques^{18, 39-41} and in congophilic amyloid angiopathy.⁴² The apoE forms a complex with A both in vitro and in vivo,^{26, 43-45} and both apoE and LRP are associated with A deposits in the AD brain (Figure 2). Importantly, cellular uptake of A/apoE complexes has been demonstrated to occur through LRP in several systems.^46-47

₂M AND AD

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₂-Macroglobulin is a tetrameric complex that acts as a pan-protease inhibitor through a unique trapping mechanism. When a protease cleaves one of several amino acids in a bait region, a marked conformational alteration occurs that sterically traps the protease and makes ₂M a ligand (referred to as ₂M*) for LRP endocytosis and clearance. It has been demonstrated that ₂M* binds A⁴⁸ and alters the likelihood of A to cause fibrillogenesis or to display in vitro toxic effects.^49-50 It also has been shown that A/₂M* complexes can be metabolized⁵¹ or cleared via an LRP-mediated process.^52-53 One other aspect of ₂M/LRP function warrants mention. There is evidence⁵⁴ that LRP can act to enhance antigen presentation by monocytes after ₂M complexes are internalized by LRP. It is possible that LRP plays a role in presenting ₂M/A complexes to the immune system. Recent data⁵⁵ suggesting that immune responses to A can modulate A deposition in transgenic models make this an intriguing speculation.

Recently, 2 different polymorphisms in the A2M gene have been genetically linked to increased risk for AD.^56-57 The first polymorphism is a pentanucleotide deletion near an intronic splice site postulated to alter splicing near the critical bait region. The deletion was found to be a risk factor in an analysis of a large number of sibships and small families selected for late-onset AD.⁵⁶ The second polymorphism, an Ile-Val interchange at position 1000, is near the active site. Homozygosity for the rare Val allele was associated with a modestly increased risk for AD in a large case-control study⁵⁷ using a hypothesis forming–hypothesis testing study design with 2 separate populations. The polymorphisms are not in linkage disequilibrium with one another. Other studies^58-61 have provided conflicting results, and, unlike APOE, neither polymorphism appears to be a strong risk factor for AD in the general population. We believe that the importance of these genetic associations is to reinforce the potential role of ₂M in AD pathobiology.

LRP INTERACTS WITH APP

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Recent data suggest that, in addition to the relationship between LRP and putative A clearance mechanisms, there may be direct interactions between LRP and APP itself. Isoforms of APP containing Kunitz protease inhibitor (APP751 and APP770) are ligands for LRP, and APP is bound and internalized by LRP.^62-63 Whether or not this directly impacts A production is not yet clear, but since recent data⁶⁴ suggest that endocytosis of APP is an important step in A synthesis in some systems, it is plausible that LRP-APP interactions could affect A generation. Indeed, prolonged treatment of cells with receptor-associated protein, which blocks LRP, dramatically reduces A production in culture, while increasing LRP increases A production.⁶⁵ Additional data implicate an indirect interaction between LRP and APP via intracellular adapter proteins. The carboxy terminal of LRP interacts with an adaptor protein, Fe65, in isolated protein coprecipitation experiments⁶⁶; Fe65 contains 2 distinct protein interaction domains; one interacts with LRP and the other is known to interact with APP.^67-71 An analogous situation has been suggested for another adapter protein called disabled.^{66, 72} These observations raise the possibility that LRP can modulate the intracellular trafficking of APP.

LRP POLYMORPHISMS: IMPLICATED AS GENETIC RISK FACTORS FOR AD

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Because of the multiple relationships between LRP and AD pathobiological findings, the LRP gene has been tested as a "candidate gene" in late-onset AD. Two common polymorphisms in the LRP gene have been studied, neither of which alters the coding region of the protein: a tetranucleotide repeat in the 5' region and a silent polymorphism in exon 3. Although data on the tetranucleotide repeat in the 5' region of LRP are not consistent among studies,^73-76 Kang and colleagues⁷⁷ found an association between a risk for AD and a silent polymorphism in exon 3 of LRP that has been confirmed by our studies⁷⁸ and others.⁷⁹

In summary, our overarching hypothesis is that LRP plays an important role in determining the balance between A synthesis and clearance mechanisms (Figure 3). A remarkable convergence of data relating AD pathophysiology and LRP supports this hypothesis: (1) LRP^{18, 80-81} and multiple LRP ligands are associated with senile plaques^{24, 81-83}; (2) LRP is the primary apoE receptor in neurons, APOE is a genetic risk factor for AD, and apoE is present on senile plaques^{18, 25}; (3) LRP can bind and clear apoE/A complexes^46-47; (4) LRP is the major ₂M receptor in the brain, and A2M may be a genetic risk factor for AD^56-57; (5) LRP can bind and clear ₂M/A complexes^48-49,52-53; (6) LRP interacts with isoforms of APP that contain the Kunitz protease inhibitor domain,^62-63 and blocking LRP in vitro decreases A production⁶⁵; (7) the C-terminus of LRP interacts with intracellular adaptor proteins that also bind the C-terminus of APP^{66, 72}; (8) LRP mediates the neurite outgrowth response of neurons to apoE^32-33 and ₂M⁸³; and (9) the LRP gene on chromosome 12 has been suggested as a genetic risk factor for AD.^77-78 We suggest that strategies aimed at manipulating LRP activity in the central nervous system may prove beneficial in enhancing A clearance and hence altering the imbalance of A synthesis and clearance that leads to A deposition in late-onset AD.

View larger version (19K): [in this window] [in a new window] Figure 3. Postulated apolipoprotein E (apoE), low-density lipoprotein receptor–related protein (LRP), 2-macroglobulin (2M), and -amyloid (A) interactions. In the extracellular compartment, apoE, 2M, and amyloid precursor protein (APP) interact with LRP binding domains. Adaptor proteins, which potentially provide a scaffolding for APP-LRP interactions, are illustrated in the intracellular compartment.

AUTHOR INFORMATION

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Accepted for publication October 6, 1999.

Supported by grant AG12406 from the National Institutes of Health, Bethesda, Md, and a grant from the American Health Assistance Foundation, Rockville, Md.

Corresponding author: Bradley T. Hyman MD, PhD, Alzheimer Disease Research Laboratory, Massachusetts General Hospital, 149 13th St, Room 6405, Charlestown, MA 02129 (e-mail: B_Hyman{at}helix.mgh.harvard.edu).

From the Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Boston (Drs Hyman and Rebeck), and The Holland Laboratory, American Red Cross, Rockville, Md (Dr Strickland).

REFERENCES

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