Apolipoprotein E receptor pathways in Alzheimer disease.

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Apolipoprotein E receptor pathways in Alzheimer disease Vanessa Schmidt, Anne-Sophie Carlo and Thomas E. Willnow∗ Alzheimer disease (AD) is the most common neurodegenerative disease affecting millions of patients worldwide. According to the amyloid cascade hypothesis, the formation of neurotoxic oligomers composed of amyloid-β (Aβ) peptides is the main mechanism that causes synaptic dysfunction and, eventually, neuronal cell death in this condition. Intriguingly, apolipoprotein E (apoE), the most important genetic risk factor for sporadic AD, emerges as a key factor that contributes to many aspects of the amyloid cascade including the clearance of Aβ from brain interstitial fluid and the ability of this peptide to form neurotoxic oligomers. Central to the activity of apoE in the healthy and in the diseased brain are apoE receptors that interact with this protein to mediate its multiple cellular and systemic effects. This review describes the molecular interactions that link apoE and its cellular receptors with neuronal viability and function, and how defects in these pathways in the brain promote neurodegeneration. © 2014 Wiley Periodicals, Inc. How to cite this article:

WIREs Syst Biol Med 2014, 6:255–270. doi: 10.1002/wsbm.1262

INTRODUCTION

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lzheimer disease (AD) is a neurodegenerative disorder and the most common form of age-related dementia. Pathological hallmarks of the disease are neurofibrillary tangles of hyperphosphorylated tau, a protein normally associated with microtubules, as well as extracellular plaques composed of a peptide termed amyloid-β (Aβ). Both types of aggregates are believed to elicit neurotoxicity and eventually cell death, the reason for progressive decline of cognitive abilities in affected individuals. The incidence of AD is rapidly rising, largely owing to an increasing life expectancy in industrialized and in developing countries. Less than 1% of cases are caused by inheritable monogenic defects resulting in early-onset AD. The vast majority of patients are inflicted by the sporadic (late-onset) form of the disease. The etiology of late-onset AD (LOAD) is less clear, but likely originates from a combination of genetic and environmental factors determining individual risk. Disturbingly, common metabolic disorders, particularly in cholesterol ∗

Correspondence to: [email protected]

Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany Conflict of interest: The authors have declared no conflicts of interest for this article.

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homeostasis, emerge as major risk factor for onset and progression of neurodegeneration in the human population.1 However, the molecular mechanisms whereby dysregulation of cholesterol homeostasis provokes noxious insults to the brain in AD remain incompletely understood. In this review, we describe molecular pathways that link systemic and cellular cholesterol homoeostasis with neuronal functions, and we discuss current concepts on how alterations in the cholesterol-handling machinery in the brain aggravate neurodegenerative processes.

THE AMYLOID CASCADE HYPOTHESIS The ‘amyloid cascade’ hypothesis represents a widely accepted concept to describe the cellular events underlying neurodegenerative processes in AD.2,3 Pivotal to this hypothesis is the amyloid precursor protein (APP), a 110- to 130-kDa type 1 transmembrane glycoprotein of poorly characterized function. It is expressed in three isoforms APP695 , APP751 , and APP770 , with APP695 being expressed in neurons. In a natural process that occurs in many cell types, APP is proteolytically broken down in two alternative pathways, amyloidogenic and nonamyloidogenic, to produce multiple fragments

© 2014 Wiley Periodicals, Inc.

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from the extracellular, the intracellular, and the transmembrane region of the precursor polypeptide (Figure 1(a)). The meaning of APP processing is still a matter of debate, but it likely serves to produce biologically active peptides that regulate various aspects of neuronal viability and function (Box 1). BOX 1 PROPOSED FUNCTIONS OF APP PROCESSING PRODUCTS The physiological relevance of APP proteolysis is under intense investigation and numerous functions have been assigned to the precursor and its processing products. The reader is referred to recent reviews on this subject.4,5 Among other functions, APP acts as cell adhesion molecule, whereas soluble (s) APPα cooperates with the epidermal growth factor receptor pathway to stimulate neuronal proliferation via extracellular signal-regulated kinase and protein kinase B signaling. In addition, sAPPα activates high-conductance K+ channels and cGMPdependent protein kinase to protect neurons from excitotoxicity. The cytoplasmic tail of fulllength APP as well as the membrane-associated carboxyl-terminal fragments CTFα and CTFβ interact with multiple adaptors and signaling molecules involved in cellular differentiation pathways (e.g., JIP, X11, and Dab1). Oligomeric forms of Aβ impair synaptic plasticity by inducing removal of glutamate receptors from the synaptic plasma membrane, suggesting a physiological role for Aβ as a modulator of synaptic activity. Finally, the soluble intracellular domain of APP (AICD) may act as transcriptional regulator by association with the adaptor Fe65 and histone acetyltransferase Tip60 in the nucleus.

While the physiological relevance of APP processing is still a matter of debate, the pathophysiological consequences are obvious. Amyloidogenic processing liberates short amino acid peptides of 37to 43-amino acid length from a region encompassing part of the transmembrane and the extracellular domains in APP. These Aβ peptides aggregate to soluble oligomers and senile plaques, characteristics of the diseased brain (Figure 1(b)). According to the amyloid cascade hypothesis, the extent of Aβ production and association to neurotoxic aggregates is the determining factor that drives neurodegeneration in AD. This hypothesis receives support from 256

rare inheritable forms of the disease (familial AD, FAD). FAD is caused by mutations in three genes encoding for APP or presenilin-1 and -2, components of the γ -secretase complex responsible for proteolytic release of Aβ from the carboxyl-terminal APP fragment CTFβ (Figure 1(a)).6 Typically, FAD mutations are associated with an overall increase in the production of Aβ peptides or with a shift toward generation of the more amyloidogenic variant Aβ 42 that is prone to aggregation.7 Down syndrome (trisomy 21) provides additional evidence that the rate of Aβ production determines the progression of neurodegeneration. Thus, increased substrate concentration due to a third copy of the APP gene (located on human chromosome 21) is sufficient to significantly increase the risk of AD in affected individuals.8

CHOLESTEROL METABOLISM AS RISK FACTOR OF SPORADIC AD Given the pathological significance of amyloidogenic processing in FAD, extensive efforts have been undertaken to identify factors that promote this pathway as an underlying cause of LOAD as well. Among the many biological concepts studied, brain cholesterol metabolism emerged as an important pathway to modulate neurodegenerative processes and the risk of AD. The brain contains a major portion of the bodily cholesterol (approximately 25%).9 The lipid mainly serves for synthesis of cell membranes, of particular importance for the formation of the extensive axonal and dendritic extensions of neurons and for maturation of synapses.10 Because of the blood–brain barrier (BBB), little brain cholesterol originates from the circulation but mostly stems from local production in the nervous system. Although neurons are able to produce their own cholesterol, they also require uptake from exogenous sources. Mainly, neurons receive exogenous cholesterol from astrocytes that release the lipid bound to an apolipoprotein (apo) called apoE (Figure 2). Structurally, lipidated apoE particles resemble lipoproteins that transport cholesterol and other lipids in the circulation.11 ApoE-containing lipoproteins in the brain interstitial fluid (ISF) are sequestered by apoE receptors on neurons, resulting in the cellular uptake and utilization of the lipid load (Figure 2). Neurons express a variety of apoE receptors, highlighting the complexity of apoE uptake pathways in this cell type (Box 2). Ample evidence links cholesterol metabolism to the risk of neurodegeneration. First, epidemiological studies suggest that high serum cholesterol



WIREs Systems Biology and Medicine

Apolipoprotein E receptor pathways in Alzheimer disease

(a)

(b)

FIGURE 1 | The amyloid cascade hypothesis. (a) Amyloid precursor protein (APP) undergoes two alternative processing pathways.2 In the nonamyloidogenic pathway, APP is first cleaved within the amyloid-β (Aβ) peptide sequence by a protease activity called α-secretase (α) that produces soluble (s) APPα from the APP extracellular domain and a membrane-anchored fragment CTFα. Subsequently, γ -secretase activity (γ ) cleaves CTFα into peptide P3 and the soluble APP intracellular domain (AICD). The amyloidogenic pathway is initiated by the cleavage of APP by β-secretase (β-site APP-cleaving enzyme-1, BACE1) at the amino-terminal end of the Aβ sequence followed by γ -secretase cleavage at its carboxyl terminus. These steps produce Aβ peptides of 37- to 43-amino acid length, as well as sAPPβ and the AICD. (b) APP processing produces monomeric Aβ molecules that are released into the extracellular space where they aggregate into neurotoxic oligomers. According to the amyloid cascade hypothesis, the concentration of toxic Aβ species in the brain is the crucial factor for induction of neuronal cell death. Levels of toxic Aβ oligomers are influenced by the kinetics of APP processing and Aβ aggregation, and by the rate of clearance of monomeric Aβ molecules.

levels (hypercholesterolemia) are associated with an increased risk of dementia and that a 70% reduction in incidence of AD can be seen in patients treated with statins, drugs that block the endogenous cholesterol biosynthesis.12 Similar observations have been made in animal models treated with these substances.13 Second, modulating the cellular cholesterol homeostasis, for example, by manipulating expression of the ATP-binding cassette transporter A1 (ABCA1) or acyl-coenzyme A acetyltransferase (ACAT), impacts Aβ production in cells and in vivo.14,15 Third, several genes encoding components of the systemic and cellular brain cholesterol homeostasis have been associated with the occurrence of sporadic AD in human cohorts. Chief among all genetic risk factors is APOE. It is present in three allelic variants in the human population termed 2, 3, and 4. Carriers homozygous for 4 are at an eightfold higher risk to develop AD when compared with noncarriers.16 Several mechanisms are discussed whereby high cholesterol levels may promote AD progression, including damage to the cerebral vasculature, alterations of BBB permeability, or changes in cholesterol content of neuronal membranes that impact synaptic activity.10 With particular relevance to this review, molecular interactions of apoE and its receptors with pathways in amyloidogenic Volume 6, May/June 2014

processes have also been uncovered. In the following, we will discuss these interactions that affect virtually every step in the amyloid cascade from Aβ production and clearance, to aggregation, to neurotoxicity, and we describe how alterations in these interactions contribute to an increased risk of neurodegeneration.

BOX 2 STRUCTURAL ORGANIZATION OF apoE RECEPTORS Two main classes of receptors mediate the cellular uptake of apoE-containing lipoproteins in the brain and in peripheral tissues. These receptors are members of the low-density lipoprotein receptor (LDLR) or the vacuolar protein sorting 10 protein (VPS10P) domain receptor gene families, two structurally related groups of endocytic receptors. Both groups encompass type 1 transmembrane proteins with amino-terminal domains involved in ligand binding. Their carboxyl-terminal tails harbor recognition sites for adaptor proteins involved in coated-pit endocytosis and intracellular protein trafficking to sort these receptors (and their cargo) along the endocytic path. The


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main ligand-binding region in the LDLR and related proteins are clusters of complement-type repeats. The common ligand-binding domain in VPS10P domain receptors is the VPS10P domain, a module first identified in the yeast VPS10P. SORLA (sorting protein-related receptor with Atype repeats) is unique as it is a chimeric protein harboring both types of ligand-binding modules. Additional functional domains in the receptors encompass motifs involved in protein–protein interaction (leucine-rich domain, epidermal growth factor-type repeat, and fibronectintype III domain) or in discharge of ligands in endocytic compartment (β-propeller). Only gene family members covered in this article are depicted. All receptors bind apoE (not shown for SORCS1). With relevance to this review, LRP1 (LDL receptor-related protein 1), LRP1B, ApoER2 (apolipoprotein E receptor 2), SORLA, and SORCS1 (sortilin-related receptor CNS expressed 1) have also been shown to interact with APP. LRP1 and the LDLR bind soluble Aβ.

CONTROL OF APP PROCESSING RATES Modulation of Secretase Activities Consecutive cleavage of the APP polypeptide chain by β- and γ -secretases produces Aβ peptides (Figure 1(a)). Accordingly, these proteases control rate-limiting steps in the amyloid cascade and they are considered prime targets for therapeutic intervention. Mainly, the kinetic of β-secretase activity has been determined with recombinant protein17,18 or in 258

cell and tissue extracts19 using artificial peptide substrates. Assuming Michaelis–Menten kinetics, these studies calculated rather poor kinetic parameters for BACE1 (Km 5–7 μM).17,19 Km values were identical in AD compared with healthy brain preparations. However, the V max was significantly increased, suggesting that some mechanisms enhance BACE1 activity (but not BACE levels) in the diseased brain.17 One of these mechanisms may be high cholesterol content of the cell membranes. BACE1 is an aspartic acid protease and an integral membrane protein. A significant fraction of BACE1 molecules in cells is associated with cholesterol-rich microdomains in the cell membrane (lipid rafts). A high content in membrane cholesterol increases the association of BACE1 with APP in lipid rafts and promotes amyloidogenic cleavage.20 In contrast, reducing the cellular cholesterol concentration causes a shift of BACE1 from raft to nonraft fractions of the membrane, and reduces enzyme activity.21 A similar effect of the cholesterol content on lipid raft association and activity has been shown for γ -secretase.22,23 A second mechanism how the cholesterol homeostasis may affect BACE1 activity came with the characterization of SORLA, an apoE receptor expressed in neurons in cortex, hippocampus, and cerebellum (Box 2). A link between SORLA activity and AD was initially suggested by work that documented reduced expression of this protein in the brain of some individuals with sporadic AD.24 In addition, epidemiological studies showed association of the human gene (SORL1) with risk of the disease in several ethnicities.25 Experimental studies documented direct binding of SORLA to APP, an interaction that protects the precursor from proteolytic processing.26,27 Consequently, loss of SORLA expression in mouse models increased,28,29 while overexpression of the receptor in cell lines decreased Aβ production.25,30 This inverse correlation between SORLA activity and APP processing rates provided an explanatory model for the increased risk of AD seen in individuals with low receptor levels.24 Quantitative biochemical studies combined with mathematical modeling established a kinetic model of amyloidogenic processing, and the influence by SORLA on this process.31 Contrary to previous hypotheses, these studies demonstrated that BACE1 does not follow Michaelis–Menten kinetics but represents an allosteric enzyme that requires cooperativity by APP oligomerization for efficient processing. Allosteric enzymes are characterized by the existence of several substrate-binding sites whereby occupation of the first site facilitates binding of the next substrate molecule by increasing the affinities of the vacant binding site(s). Binding of SORLA to APP





FIGURE 2 | Cellular brain cholesterol transfer pathways. In astrocytes, free cholesterol (FC) is associated with newly synthesized apolipoprotein E (apoE) (E) to form a lipoprotein particle that is released into the brain interstitial fluid (ISF). In addition, astrocytes also release FC via the ATP-binding cassette transporter A1 (ABCA1) that associates with apoE-containing lipoproteins in the extracellular fluid to further increase their lipid content. Conversion of FC to cholesterol ester (CE) by acyl-coenzyme A acetyltransferase (ACAT) counteracts the lipidation of apoE. From the ISF, apoE-containing lipoproteins are delivered to neurons via apoE receptors (E-R) that bind the apolipoprotein and mediate endocytic uptake of the protein–lipid complex. In endosomes, E-Rs discharge their ligand and return to the cell surface (not shown), whereas lipoproteins move to lysosomes where apoE and lipids are catabolized.

monomers prevents APP dimer formation in cultured cells and in the brain, eliminating the preferred form of the substrate and causing BACE1 to switch to a less efficient nonallosteric mode of action.31 This model is supported by prior evidence documenting the ability of APP and of BACE1 to form homodimers,32,33 and by the finding that BACE1 dimers have a higher catalytic activity than BACE1 monomers.33 Conceptually, an allosteric mode of action may be of particular pathophysiological relevance as allosteric enzymes act by an on–off switch mechanism enabling rapid adaptation of enzyme activity to even subtle changes in substrate concentration. Such an allosteric mode of action was likely missed in earlier studies that used artificial peptides rather than APP as BACE1 substrates.31 The kinetic model for BACE1 cleavage of APP is detailed in Figure 3. Kinetic parameters for γ -secretase activity in cell and tissue extracts have also been determined assuming Michaelis–Menten kinetics.34 Whether this protease activity is also influenced by dimer formation of its substrate CTFβ remains to be shown.

ApoE Receptors Regulate Intracellular APP Transport Secretases reside in distinct organelles of the cell and the ability of APP to enter or avoid certain cellular Volume 6, May/June 2014

compartments constitutes another factor that determines its processing fate.35,36 Thus, newly synthesized APP molecules follow the constitutive secretory pathway of the cell and move from the endoplasmic reticulum through the Golgi and trans-Golgi network (TGN) to the plasma membrane (Figure 4(a)). At the plasma membrane, most APP molecules are cleaved by α-secretase to release sAPPα. However, some precursor molecules escape nonamyloidogenic processing and internalize from the cell surface through clathrinmediated endocytosis. Internalization is guided by an NPxY motif in the cytoplasmic tail of APP37 that facilitates interaction with the clathrin adaptor complex AP2.38 From early endosomes, APP typically moves to the late endosomal/lysosomal compartment. Extensive experimental evidence suggests that this fraction of endocytosed APP molecules is subjected to amyloidogenic processing.39–42 For example, blocking APP endocytosis by deletion of its NPxY motif43 or by overexpression of dominant-negative dynamin mutants impairs Aβ production.44,45 The predominant localization of β-secretase in endosomal compartments46,47 and its requirement of an acidic milieu (as in endocytic vesicles) for its activity support this model.48 Many studies have focused on elucidating the mechanisms that control intracellular APP transport, sparked by observations that defects in


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FIGURE 3 | The apolipoprotein E (apoE) receptor SORLA (sorting protein-related receptor with A-type repeats) determines monomeric versus dimeric processing of APP by BACE1. In the preferred mode of action, BACE1 monomers form homodimers that act on APP homodimers to produce CTFβs (dimer processing). The association of SORLA with APP monomers prevents APP dimer formation, requiring BACE1 monomers to act on the nonpreferred monomeric APP substrate (monomer processing). Association of BACE1 with APP is fostered by the membrane cholesterol content (C) promoting sequestration of enzyme and substrate in lipid rafts.

neuronal trafficking processes may be causative of enhanced amyloidogenic processing in sporadic AD.49 Remarkably, receptors of the LDL receptor and the VPS10P domain receptor gene families emerged as regulators of APP sorting into and out of the endosomal compartments. This function is mediated by their ability to interact with APP directly or through cytosolic adaptor proteins. Internalization of APP from the cell surface is modulated through its interaction with the LRP1 (Figure 4(b)). This interaction involves the adaptor protein Fe65 that simultaneously binds to NPxY motifs in the cytoplasmic tails of APP and LRP1, forming a trimeric protein complex.50,51 Interaction of APP with LRP1 at the cell surface accelerates endocytosis of the precursor protein and enhances Aβ production in cells52,53 and in mouse models of AD.54 LRP1-induced internalization of APP is counteracted by ApoER2 and LRP1B, two related receptors that compete with LRP1 for APP binding (Figure 4(b)).55–57 Interaction of ApoER2 with APP proceeds through Fe65 and through an extracellular ligand F-spondin, which mediate the complex formation between the cytoplasmic and extracellular domains of ApoER2 and APP, respectively.56,57 260

The mode of interaction of LRP1B with APP is unclear at present. Because ApoER2 and LRP1B are more slowly endocytosed than LRP1, the association of APP with ApoER2 or LRP1B results in APP sequestration on the cell surface and in a decrease in Aβ production55–58 (Figure 4(b)). Recently, the Fe65-mediated interaction of two further receptors of the LDL receptor gene family, namely LRP2 and the very-low-density lipoprotein receptor (VLDLR), with APP has been reported,59,60 further extending the repertoire of potential APP interaction partners at the cell surface. Along with controlling entry of APP into endosomes, apoE receptors also modulate the exit of the precursor protein from this organelle, counteracting amyloidogenic processing as best exemplified for the VSP10P domain receptor SORLA. VPS10P domain receptors are distinct from classical endocytic receptors inasmuch as receptor molecules internalized from the cell surface into endosomes do not efficiently recycle back to the plasma membrane (such as LRPs). Rather, receptors such as SORLA move retrogradely to the TGN and, thereafter, continue to shuttle between TGN and early endosomes.30,61 Several adaptor complexes mediate





(a)

(b)

FIGURE 4 | Pathways of intracellular APP transport. (a) Newly synthesized APP molecules traverse the trans -Golgi compartment (TGN) to the plasma membrane where most precursor molecules are cleaved by α-secretase producing sAPPα. Nonprocessed precursors internalize from the cell surface via clathrin-mediated endocytosis. From early endosomes, APP moves to endosomal compartments for amyloidogenic processing through sequential cleavage by β- and γ -secretases generating sAPPβ and amyloid-β (Aβ). (b) Trafficking of APP in neurons is controlled by apoE receptors. At the cell surface, association of APP with LRP1 (step 1) stimulates endocytic uptake and intracellular processing of APP to Aβ in endosomes (step 2). In contrast, interaction with the slow-endocytosing receptor apolipoprotein E receptor 2 (ApoER2) delays endocytosis of APP (step 3). Binding of APP to SORLA in endosomes results in retrograde sorting of APP to the TGN (step 4), counteracting amyloidogenic processing in the endocytic compartment. LRP1B acts similar to ApoER2 in delaying endocytosis of APP (not shown).

this shuttling by targeting specific motifs in the cytoplasmic domain of SORLA.30,61 These adaptors include Golgi-localizing, γ -adaptin ear homology domain, ARF-interacting proteins (GGA1, GGA2, and GGA3), and monomeric clathrin adaptors that sort target proteins from the TGN to endosomes (anterograde sorting). Retromer is a multiprotein complex that mediates retrograde sorting of SORLA from endosomes back to the TGN.62,63 Phosphofurin acidic cluster sorting protein 1 (PACS1) may mediate both retrograde as well as anterograde Golgi-toendosome transport.64 Adaptor interactions proved crucial for SORLA-dependent sorting and processing of APP, as deletion of adaptor-binding sites in the receptor tail caused the inability to sort to the TGN and resulted in aberrant routing and enhanced processing of APP.30,61,63,65 Additional evidence to support the importance of SORLA and adaptor interaction for AD stems from the analysis of the retromer complex that is composed of VPS35, VPS29, VPS26, and the sorting nexins 1 and 2 (reviewed in Ref 66). VPS35 and VPS26 are poorly expressed in Volume 6, May/June 2014

AD brains,67 and disruption of Vps35 in mice results in synaptic dysfunction associated with elevated Aβ levels.68 Taken together, the available data support a model in which interaction of SORLA with APP not only prevents APP dimer formation but also triggers rerouting of internalized precursor molecules from endosomes back to the TGN, reducing amyloidogenic processing (Figure 4(b)). Similar roles in trafficking of APP and of BACE1 have been suggested for sortilin and SORCS1, but the underlying mechanisms warrant further clarification.69–72

Aβ AGGREGATION AND CATABOLISM ApoE Affects Aggregation of Aβ Following secretion into the brain ISF, Aβ monomers associate to soluble oligomers and the intermediates to insoluble fibrils in senile plaques. In recent years, the process of Aβ oligomer formation received major attention as oligomers are now considered the major toxic species in AD. Thus, in patients synaptic loss is


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better correlated with levels of soluble Aβ than with insoluble amyloid fibrils.73 Also, soluble aggregates are in orders of magnitude more toxic to neurons than fibrils,74,75 and they decrease the number of synapses and impair learning performance in animal models.76,77 Biophysical methods have been applied to study the kinetics of Aβ oligomerization in vitro and to develop mathematical models to describe this process.78,79 In the oligomerization phase, Aβ monomers spontaneously self-assemble to dimers and trimers, and further to low-molecular-weight oligomers. This process proceeds considerably faster with Aβ 42 than with Aβ 40 , in line with the enhanced amyloidogenic properties of the Aβ 42 variant.80 The rapid phase of oligomerization is followed by a lag phase of clustering of oligomers, and finally by the growth phase of protofibrils and fibrils.80 Not surprisingly, the process of Aβ oligomerization is dependent on various experimental conditions such as Aβ concentration, temperature, and pH. In the ISF, it is also affected by the presence of apolipoproteins that bind Aβ monomers and modulate their aggregation behavior. For example, apoE directly binds to Aβ 81 and promotes fibril formation.82–84 The affinity for Aβ is dependent on the lipidation status of the apolipoprotein with lipid-rich apoE being a better binder than its lipid-poor form.85 Absence of apoE in mice decreases plaque deposition.86 The aggregationpromoting properties of apoE are isoform-specific as more plaques are formed in mice expressing human apoE4 compared with apoE3.87 Apolipoprotein J (clusterin) is another apolipoprotein that was identified as major genetic risk factor of AD in genome-wide association studies.88 Binding to clusterin protects Aβ from proteolytic degradation89 and, similar to apoE4, aggravates Aβ aggregation and neurite dystrophy in vivo.90 While mice genetically deficient for either Apoe86 or clusterin87 show less amyloid burden than controls, mice doubly deficient for both proteins are more severely affected by plaque deposition.91 Possibly, additional functions for apoE and clusterin may be unmasked in the absence of both proteins. These functions may include promotion of clearance of Aβ by apolipoprotein receptors as discussed below.

Cellular Catabolism of Aβ Secreted Aβ molecules are subject to catabolism, affecting the concentration of monomers available for oligomer formation (Figure 1(b)). The pathophysiological relevance of catabolic pathways is underscored by findings that the average clearance rates for Aβ 40 and Aβ 42 are reduced by 30% in individuals with sporadic AD when compared with healthy 262

controls.92 A major mechanism for catabolism of Aβ is degradation by proteases such as neprilysin, insulin-degrading enzyme, or cathepsin B, and the reader is referred to a recent review on this subject.93 In the following, we focus on the cellular uptake of Aβ by receptors of the LDL receptor and VPS10P domain receptor gene families as another important pathway for catabolism of this peptide. In the brain parenchyma, endocytic pathways in astrocytes, in microglia, and in neurons are implicated in cellular uptake and lysosomal degradation of Aβ, both in free form and when bound by apoE (reviewed in Ref 94). The main receptors implicated in endocytosis of free Aβ are the LDL receptor and LRP195,96 (Figure 5(a)). Binding of Aβ to LRP1 is facilitated by heparin sulfate proteoglycans at the cell surface.97 In addition, both receptors also clear Aβ when bound to apoE,98–100 a function shared by the VPS10P domain receptor sortilin101 (Figure 5(b)). Experimental support for involvement of all three receptors in brain apoE catabolism stems from the fact that targeted inactivations of Ldlr, Lrp1, or Sort1 cause accumulation of apoE in the brain of mice.101–103 Although the LDL receptor mainly operates in astrocytes and microglia,95,104 LRP1 and sortilin constitute major uptake pathways in neurons.94,101 The importance of apoE in promoting cellular uptake of Aβ via apoE receptors was shown by many in vitro studies.98–100,105 The efficiency of uptake is similar with apoE3 and apoE4, in line with their similar binding properties to apoE receptors.105 Data from transgenic mouse models produced more conflicting results, but overexpression of human apoE106 or of the LDL receptor104 was shown to enhance Aβ clearance in mice. Also, pharmacological induction of Apoe expression in mice ameliorates Aβ production and plaque deposition substantiating an inverse correlation of apoE concentration with brain Aβ levels.107

BBB Export of Aβ The clearance of Aβ from the brain parenchyma is also determined by transport of the peptide across the BBB. The BBB forms along all capillaries in the brain and restricts the diffusion of macromolecules between brain ISF and blood circulation. Perivascular drainage significantly decreases with age108 and in conditions of vessel disease (as in hyperlipidemia),1,109 suggesting a causal link between metabolic disorders and risk of AD. The abundance of amyloid deposits in the wall of brain vessels seen in AD patients110 and mouse models of the disease111,112 impair BBB transport, further aggravating the built-up of toxic Aβ species in the diseased brain. Tracer studies in mice documented that the half-time of Aβ efflux is seven times faster




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FIGURE 5 | Pathways for cellular clearance and blood–brain barrier (BBB) export of free or apolipoprotein E (apoE)-bound amyloid-β (Aβ). (a) In the brain interstitial fluid (ISF), cellular uptake and lysosomal catabolism of soluble Aβ is mediated by low-density lipoprotein (LDL) receptors (LDLRs) in astrocytes and microglia, and by LRP1 in neurons. Alternatively, soluble Aβ is transported across the BBB by LRP1. In the circulation Aβ associates with a soluble fragment of LRP1 (sLRP1) preventing transfer of the peptide back into the ISF via transporters such as the receptor for advanced glycation end products (RAGE). (b) In the ISF, free Aβ may also associate with apoE (E). Complex formation reduces the extent of BBB export but promotes cellular catabolism in the brain parenchyma by apoE receptors on neurons (LRP1, sortilin) and astrocytes (LDL receptor).

than ISF bulk flow, indicating an active transport process for the peptide across the BBB.113 LRP1 on endothelial cells likely constitutes this active transport pathway as Aβ clearance is significantly impaired in the presence of receptor antagonists.113,114 LRP1mediated export mainly proceeds with free Aβ 96 (Figure 5(a)) and is impaired by association of the peptide with apoE (Figure 5(b)).115 In line with the higher risk of AD being conferred by the APOE4 genotype, the apoE4 isoform inhibits clearance of Aβ more profoundly than apoE3 in various mouse models of the disease.116,117 A soluble form of LRP1 (sLRP1) produced by shedding of the extracellular domain of the receptor in hepatocytes circulates in plasma and constitutes a major binding protein for plasma Aβ.118 Potentially, sLRP1 provides a ‘sink’ for plasma Aβ, reducing the extent of transport back into the brain (reviewed in Ref 119) (Figure 5(a)). Overexpression of the LDL receptor in mice also increases BBB export of Aβ, suggesting a similar function like LRP1 in brain capillary transport of the peptide.116

NEUROTOXICITY ApoE4 Fragments Are Neurotoxic Along with mediating cholesterol transport, apoE has also been shown to directly impact neuronal Volume 6, May/June 2014

viability and function. Among the many functions assigned to apoE are control of neurite outgrowth and synaptogenesis, cytoskeleton rearrangements, or modulation of synaptic transmission. In these studies, apoE3 typically improved, whereas apoE4 worsened neuronal pathology.120–122 One molecular pathway studied in details is the production of apoE fragments in neurons that cause neurotoxicity. Under normal conditions, brain apoE is mainly produced by astrocytes. However, under conditions of cell stress (such as seizures), expression of apoE can also be induced in neurons.123 Intriguingly, neuronal apoE4 is subject to intracellular proteolysis generating a fragment of the apolipoprotein that lacks the carboxyl-terminal part of the lipid-binding domain.124 When produced in cells or in mice, this fragment causes mitochondrial dysfunction and hyperphosphorylation of tau.125,126 Neuronal apoE3 is protected from this processing fate because a single amino acid change when compared with apoE4 alters its protein structure. The protease responsible for neuronal apoE4 processing is unknown at present, but suggested to be a chymotrypsin-like serine protease.126 A neurotoxic role for apoE4 fragments is intriguing as it represents another possible molecular explanation for the isoform-specific effects of apoE on risk of AD. Also, it links components of the cholesterol transport machinery to tau pathology, the second major pathological feature of the AD brain.


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FIGURE 6 | ApoE4 causes removal of apolipoprotein E (apoE) receptors from the neuronal cell surface and promotes synaptic dysfunction. Amyloid-β (Aβ) induces the internalization of NMDA receptors (NMDARs) from the postsynaptic membrane, resulting in suppression of synaptic activity (step 1). Binding of reelin to the apoE receptor 2 (ApoER2) results in an intracellular signal cascade that prevents Aβ-induced internalization of NMDAR (step 2). The protective function of the reelin–ApoER2 pathway is inhibited by binding of apoE4 to ApoER2, resulting in intracellular accumulation of apoE4/ApoER2 complexes and depletion of ApoER2 molecules from the postsynaptic membranes (step 3).

ApoE4 Impairs the Protective Function of apoE Receptors at the Synapse Oligomeric forms of Aβ impair synaptic plasticity by inducing the internalization of glutamate receptors from the synaptic plasma membrane.127,128 Although the molecular mechanism still warrants clarification, this observation suggests a physiological role for Aβ as a modulator of synaptic activity and aberrant suppression of synaptic transmission by excessive Aβ production in the AD brain. In support of this hypothesis, synaptic activity is a major driving force for Aβ production in hippocampal slice cultures129 and in the brain in vivo,130,131 apparently providing a negative feedback loop for synaptic activity. An unexpected role for apoE receptor in protection from neurotoxicity came with the observation that binding of reelin, a secreted signaling factor to ApoER2, prevents synaptic suppression by Aβ.132 This neuroprotective function of the reelin pathway is lost in the presence of apoE4 but not apoE3. According to current models (Figure 6), binding of apoE4 to ApoER2 results in intracellular accumulation of receptor–ligand complexes, thus depleting reelin receptors from the neuronal cell surface. In contrast, binding of apoE3 to the receptor

results in efficient recycling of receptor and ligand back to the cell surface, and in sustained activity of the reelin pathway.133

CONCLUSION A large body of work has firmly established a causal link between apoE activity and amyloidogenic processes in AD. In particular, loss- and gainof-function models in cell lines and transgenic mice have been instrumental in deciphering the molecular interactions between this component of the cholesterol-handling machinery and the APP pathway in the brain. Obviously, experimental systems with overexpression or complete loss of activity of various risk factors do not necessarily reflect the situation in the diseased human brain where incremental changes in activity of various players may determine the risk of AD over the course of a lifetime. Clearly, systems biology approaches combining quantitative biochemical data with mathematical modeling will be helpful to assess the quantitative contribution of various factors to disease progression, and to develop algorithms for the prediction of individual risk.

ACKNOWLEDGMENTS Work in the authors’ laboratory was supported by grants from the Helmholtz-Association (HelMA, iCEMED), the Fritz Thyssen Foundation, and the Alzheimer Research Initiative (AFI).

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Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease.

Apolipoprotein E in Alzheimer's disease: an update.

Vitamin E, memantine, and Alzheimer disease.

Mapping the effect of the apolipoprotein E genotype on 4-year atrophy rates in an Alzheimer disease-related brain network.

The role of apolipoprotein E in neurodegeneration and cardiovascular disease.

Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ɛ4 Carriers.

Genetic association of apolipoprotein E polymorphisms with inflammatory bowel disease.

Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders.

A human apolipoprotein E mimetic peptide reduces atherosclerosis in aged apolipoprotein E null mice.

Apolipoprotein E ε4 is superior to apolipoprotein E ε2 in predicting cognitive scores over 30 months.

Molecular Imaging of the Nicotinic Cholinergic Receptor in Alzheimer Disease.

Alois Alzheimer--Alzheimer disease.

Apolipoprotein E and neurocognitive function.

Apolipoprotein E increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways.

Phenotypes of apolipoprotein B and apolipoprotein E after liver transplantation.

Cerebrospinal Fluid Apolipoprotein E Levels in Delirium.

Apolipoprotein E pathology in vascular dementia.

Role of apolipoprotein E in neurodegenerative diseases.

Apolipoprotein E and neurocognitive function--in reply.

Emerging Roles of Apolipoprotein E and Apolipoprotein A-I in the Pathogenesis and Treatment of Lung Disease.

E) receptor.

Protease-Activated Receptor-2 Deficiency Attenuates Atherosclerotic Lesion Progression and Instability in Apolipoprotein E-Deficient Mice.

Monocytic elastase-mediated apolipoprotein-E degradation: Potential involvement of microglial elastase-like proteases in apolipoprotein-E proteolysis in brains with Alzheimers disease.

A₁ adenosine receptor deficiency or inhibition reduces atherosclerotic lesions in apolipoprotein E deficient mice.