Biochemical Society Transactions

Models of Dementia: the Good, the Bad and the Future

Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer's disease: lessons from ApoE mouse models

Yadong Huang


ApoE4 (apolipoprotein E4) is the major known genetic risk factor for AD (Alzheimer's disease). In most clinical studies, apoE4 carriers account for 65–80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Emerging data suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to AD in multiple ways either independently or in combination with other factors, such as Aβ (amyloid β-peptide) and tau. Many apoE mouse models have been established to study the mechanisms underlying the pathogenic actions of apoE4. These include transgenic mice expressing different apoE isoforms in neurons or astrocytes, those expressing neurotoxic apoE4 fragments in neurons and human apoE isoform knock-in mice. Since apoE is expressed in different types of cells, including astrocytes and neurons, and in brains under diverse physiological and/or pathophysiological conditions, these apoE mouse models provide unique tools to study the cellular source-dependent roles of apoE isoforms in neurobiology and in the pathogenesis of AD. They also provide useful tools for discovery and development of drugs targeting apoE4's detrimental effects.

  • Alzheimer's disease (AD)
  • animal model
  • apolipoprotein E (apoE)
  • cognitive impairment
  • neurodegeneration


AD (Alzheimer's disease) causes progressive, irreversible loss of cognitive function and is characterized by two neuropathological hallmarks: extracellular amyloid plaques and intracellular NFTs (neurofibrillary tangles) [1]. AD is a complex neurodegenerative disorder that is probably caused by interactions among multiple genetic and environmental factors. Mutations in three genes, APP (amyloid protein precursor), PSEN1 (presenilin 1) and PSEN2 (presenilin 2), have been linked to early-onset (<60 years old) familial AD [24], which accounts for less than 5% of AD cases. The mutations all affect APP processing, leading to altered production of Aβs (amyloid β-peptides) [2,3]. apoE4 (apolipoprotein E4) has been genetically linked to late-onset (>60 years old) familial and sporadic AD, which account for more than 95% of AD cases, and it has a gene-dose effect on the risk and age of onset of the disease [57]. Individuals with two copies of the apoE4 allele (2% of the total population) have a 50–90% chance of developing AD by the age of 85, and those with one copy of apoE4 (15% of the total population) have ~45% chance of developing the disease [5]. By comparison, ~20% of the general population will develop AD by the age of 85 [5].

Polymorphism, structure and biophysical properties of apoE


ApoE, a 299-amino-acid glycoprotein with a molecular mass of 34200 Da, is a polymorphic protein [8]. Its three common isoforms (apoE2, apoE3 and apoE4) in humans are all products of the same gene, which exists as three alleles (ϵ2, ϵ3 and ϵ4) at a single gene locus [812]. In almost all populations, the apoE3/3 phenotype is the most common (typically ~50–70% of the population), and the ϵ3 allele accounts for the vast majority of the apoE gene pool (typically ~70–80%). The ϵ4 allele account for 10–15%, and the ϵ2 alleles 5–10%. The three isoforms differ from one another by substitutions at residues 112 and 158 [1315]. apoE3 has Cys-112 and Arg-158, whereas apoE4 has arginines at both positions, and apoE2 has cysteines.

Structure and biophysical properties

ApoE has two structural domains: the N-terminal domain (amino acids 1–191) containing the receptor binding re-gion (amino acids 135–150) and the C-terminal domain (amino acids 223–299) containing the lipid binding re-gion (amino acids 241–272) [16]. The two domains are linked by a structurally flexible hinge region (amino acids 192–222) [16]. Interaction between the C- and N-terminal domains, called domain interaction, is a unique biophysical property of apoE4 [17,18]. In apoE4, Arg-112 reorients the side chain of Arg-61 in the N-terminal domain from the position it occupies in apoE2 and apoE3, allowing it to form a salt bridge with Glu-255 in the C-terminal domain [17,18]. In apoE2 and apoE3, Arg-61 has a different conformation, and domain interaction does not occur [17,18]. Only human apoE has Arg-61; the 17 other species in which the apoE gene has been sequenced all have Thr-61 [16]. Mutation of Arg-61 to threonine or Glu-255 to alanine in apoE4 prevents domain interaction and converts apoE4 into a form like apoE3 [17,18]. ApoE4 domain interaction also occurs in living neuronal cells in culture [19]. It has been demonstrated that intramolecular domain interaction is responsible for apoE4's ability to stimulate Aβ production and potentiate Aβ-induced lysosomal leakage and apoptosis and for its susceptibility to proteolysis [2022].

Interestingly, mouse apoE contains arginine at a position equivalent to 112 in human apoE, but it lacks the critical Arg-61 that mediates domain interaction. Instead, mouse apoE contains Thr-61 [16]. Thus mouse apoE lacks domain interaction and is functionally equivalent to human apoE3. Since mouse apoE contains the equivalent of Glu-255, replacing Thr-61 with arginine introduces the domain interaction in gene-targeted mice [23].

Cellular origin-dependent effects of ApoE4 on AD pathogenesis

Astrocyte-specific regulation of apoE expression and AD

Astrocytes have long been recognized as a source of apoE [24,25]. Two distal enhancers that specify apoE gene expression in macrophages were identified in transgenic mice with specific constructs of the human apoE/CI/CI′/CIV/CII gene cluster [26]. One of these enhancers, ME-1 (multi-enhancer-1), consists of a 620-nt sequence located 3.3 kb downstream of the apoE gene. The second, ME-2, is a 619-nt sequence located 15.9 kb downstream of the apoE gene and 5.9 kb downstream of the apoCI gene. Further studies showed that ME-1 and ME-2 also drive apoE gene expression in astrocytes of the olfactory bulb, cerebellum and hippocampus in transgenic mice [27]. Expression of apoE in astrocytes is up-regulated during aging [28]. Interestingly, in mice in which EGFP (enhanced green fluorescent protein) cDNA was inserted into the mouse apoE locus immediately after the translation initiation site (EGFPapoE reporter mice), we demonstrated that a subclass of astrocytes (~25% of all astrocytes) does not express apoE [29]. In vitro and in vivo studies suggest that astrocyte-derived apoE has isoform-specific effects on Aβ production, deposition, or clearance [3034], neurite outgrowth [35], and endoplasmic reticulum stress and astrocytic function [36]. Interestingly, astrocytic apoE4 is excitoprotective, whereas neuronal apoE4 is not [37].

Neuron-specific regulation of apoE expression and AD

Initially, apoE was thought to be synthesized by astrocytes, oligodendrocytes, activated microglia and ependymal layer cells, but not by neurons in the brain [24,25]. However, CNS (central nervous system) neurons also express apoE, albeit at lower levels than astrocytes [3846]. Both apoE protein and mRNA are found in cortical and hippocampal neurons in humans [45] and in transgenic mice expressing human apoE under the control of the human apoE promoter [47]. In rats treated with kainic acid, apoE expression is induced in hippocampal neurons that survive excitotoxic stress, as determined by both in situ hybridization and anti-apoE immunohistochemistry [48]. Neuronal expression of apoE can be induced in human brains after cerebral infarction [49]. In EGFPapoE reporter mice, CNS neurons express apoE in response to excitotoxic injury [29]. ApoE is also expressed in primary cultured human CNS neurons [50] and in many human neuronal cell lines, including SY-5Y, Kelly and NT2 cells [51,52].

Cell-culture studies have also demonstrated that neuronal expression of apoE can be regulated. In SY-5Y cells, expression of apoE is down-regulated during neuronal differentiation induced by nerve growth factor and by addition of exogenous apoE to the medium [53]. Likewise, the expression of apoE in neuronal precursor NT2/D1 cells is also down-regulated by retinoic acid-induced differentiation [52]. In Neuro-2a cells stably expressing a human apoE genomic DNA construct containing a 5-kb 5′-flanking region, a 3-kb 3′-flanking region and a 3-kb tissue-specific control element [27], the baseline expression of apoE is very low. However, the conditioned medium from an astrocytic cell line (C6) or mouse primary astrocytes stimulated apoE expression by 4–10-fold [54]. Interestingly, the astroglial regulation of neuronal expression of apoE is controlled by the ERK (extracellular signal-regulated kinase) pathway [54], which participates in neuronal differentiation [53]. Furthermore, human neuronal precursor NT2/D1 cells express apoE [52]. During retinoic acid-induced differentiation of these cells into neurons, apoE expression increased initially and then diminished. However, treatment of the fully differentiated neurons with astrocyte-conditioned medium rapidly and significantly up-regulated their apoE expression [54]. Cultured mouse primary cortical and hippocampal neurons also express low levels of apoE. Astrocyte-conditioned medium rapidly up-regulated apoE expression in these cells, and the increased expression was abolished by pre-incubation with an ERK pathway inhibitor [54]. A recent study suggests that the neuronal expression of apoE is regulated by intron-3 retention and splicing [55].

Neuron-derived apoE3 and apoE4 differ in their susceptibility to proteolysis [5659] and in their effects on mitochondrial function [59], tau phosphorylation [5658,6062], lysosomal leakage [63], neurodegeneration [64,65], androgen receptor deficiency [66] and cognitive decline [6668]. As mentioned above, neuronal apoE4 is not excitoprotective, although astrocytic apoE4 is [37]. It has been hypothesized that CNS injury induces neuronal expression of apoE to participate in neuronal repair or to protect neurons from injury [8,21,22,48,6971]. This protective mechanism may be overridden in individuals carrying the detrimental apoE4 allele [8,21,22,6971].

Aβ-dependent roles of ApoE4 in AD pathogenesis

ApoE4 alters Aβ catabolism

Aβ overproduction and deposition might play a central role in AD pathogenesis [72]. In vivo, apoE is associated with neuritic amyloid plaques [7375]. In vitro, lipid-free apoE3 and apoE4 can form an SDS- and guanidine hydrochloride-stable complex with Aβs, with apoE4 complexes forming more rapidly and effectively [76,77]. In addition, apoE4 enhances zinc- and copper-induced Aβ aggregation [78]. Thus apoE seems to display isoform-specific differences in binding to the Aβ, with apoE4 binding more rapidly and effectively under certain conditions. Increased amyloid fibril formation associated with apoE4 probably triggers or exacerbates neurodegeneration and the development of AD. Previous studies in apoE-deficient mice expressing APP-V717F demonstrated that apoE is actually required for amyloid plaque formation, at least in mice [34].

However, when incubated with Aβ, poorly lipidated apoE3 or apoE4 isolated from stably transfected apoE-expressing cells yielded different results [31,32]. ApoE3 bound with a 20-fold greater affinity than apoE4 to the Aβ, suggesting that cell-derived apoE differs from purified recombinant apoE in its ability to interact with Aβs in vitro [31,32]. The avid binding of apoE3 to the Aβ may enhance clearance of the complex, preventing the conversion of Aβ into a neurotoxic species [32]. This observation may explain why apoE3 protects rat hippocampal neurons from Aβ-induced neurotoxicity [79] and why the plaque load is lower in APP transgenic mice expressing apoE3 than in those expressing apoE4 [33].

Studies of transgenic mice expressing human apoE3 or apoE4 have also provided insights into the role of apoE in Aβ metabolism. When hAPP-V717F mice were crossed on to the apoE-null background, Aβ deposition in the brain decreased dramatically, suggesting that mouse apoE enhances Aβ deposition [34,80]. However, mice expressing human apoE3 or apoE4 in the absence of mouse apoE had less Aβ deposition than mice expressing mouse apoE, suggesting that human apoE stimulates Aβ clearance [33,80]. Interestingly, apoE2 and apoE3 cleared more Aβ than apoE4 [33,81], which might be related to apoE promotion of astrocyte co-localization and degradation of deposited Aβs [82]. A recent study demonstrates that the C-terminal-truncated apoE4, which is found in AD brains [56,57], inefficiently clears Aβ and acts in concert with low levels of Aβ to elicit neuronal and behavioural deficits in transgenic mice [80]. It seems that the cognitive impairment in human APP transgenic mice depends on apoE [80,83]. Furthermore, a differential effect of neuronal and glial apoE4 on Aβ deposition and plaque formation in hAPP-V717I transgenic mice has been reported, which shows that neuronal, but not glial, apoE4 stimulates Aβ deposition and plaque formation in the hippocampus and cortex [84]. However, in another study, overexpression of apoE4 in astroglia and neurons did not alter Aβ deposition in transgenic mice [85].

On the other hand, although some studies have suggested that the main effect of apoE isoforms on AD pathogenesis is through plaque formation [33,34,86], others have provided evidence for plaque-independent mechanisms [65,68]. A recent study demonstrates that modulation of AD-like synaptic and cholinergic deficits in transgenic mice by human apoE depends on isoform, aging and overproduction of Aβs but not on plaque formation [65]. In this study, apoE4-related synaptic and cholinergic deficits (12–15 months) preceded plaque formation (19–24 months), and despite their marked difference in plaque loads (over 10-fold), old hAPP/apoE4 and hAPP/apoE3 bigenic mice (19–24 months) had comparable synaptic and cholinergic deficits [65]. Furthermore, the differential effects of apoE isoforms on hAPP/Aβ-induced cognitive impairment in 6-month-old hAPP/apoE bigenic mice were independent of plaque formation and, surprisingly, Aβ levels in the brain [68]. Based on our studies [5658], we hypothesize that the Aβ- and plaque-independent effects of apoE4 on neuronal and behavioural deficits are caused by neurotoxic effects of the apoE fragments (see below).

Aβ-independent roles of ApoE4 in AD pathogenesis

ApoE4 causes neuronal and behavioural deficits in the absence of Aβ accumulation in transgenic mice

Several transgenic mouse lines expressing apoE3 or apoE4 have been established. The NSE (neuron-specific enolase) promoter has been used to express human apoE3 or apoE4 at similar levels in neurons of transgenic mice lacking endogenous mouse apoE [64,67]. NSE-apoE4 mice showed impairments in a water maze test and in vertical exploratory behaviour not observed in NSE-apoE3 mice or wild-type controls. These impairments increased with age and were observed primarily in female apoE4 transgenic mice, suggesting that human apoE isoforms differ in their effects on brain function in vivo and that the susceptibility to apoE4-induced deficits is critically influenced by age and gender [64,67]. Morphological studies of these transgenic mouse lines demonstrated that human apoE3 prevents the age-dependent neurodegeneration seen in apoE-null mice and prevents kainic acid-induced neurodegeneration [64]. Human apoE4 is not protective [64]. Transgenic mice expressing apoE4 in astrocytes had impairment of working memory, although no significant neuropathological changes were found in the brains of these mice [87]. A recent study demonstrates that apoE4 causes age- and tau-dependent impairment of GABAergic interneurons in the hippocampus, leading to learning and memory deficits [88]. Since Aβ does not accumulate in any of these apoE isoform transgenic mouse models, these data strongly suggest an Aβ-independent role of apoE4 in causing neuronal and behavioural deficits in vivo.

ApoE4 proteolysis and neurotoxicity

It has been found that apoE4 is more susceptible to proteolytic cleavage than apoE3, as determined in vitro in transfected neuronal cells and in vivo in transgenic mice expressing apoE3 or apoE4 and by incubating recombinant apoE3 or apoE4 with partially purified apoE cleaving enzyme, a chymotrypsin-like serine protease [5658]. These apoE fragments were present at much higher levels in the brains of AD patients than in those of age- and sex-matched non-demented controls [56,57]. C-terminal-truncated fragments of apoE also appeared to accumulate in NFTs in AD brains [56].

To determine whether expression of C-terminal-truncated apoE4 in transgenic mice induces AD-like neuropathological and behavioural changes, we established transgenic mouse lines expressing various levels of apoE4(Δ272–299) with its signal peptide in CNS neurons [57,80,88]. Our results revealed that the apoE4 fragments cause AD-like neuronal and behavioural deficits in transgenic mice expressing high levels of the fragment at young ages (6–7 months) [57] or low levels of the fragment at old ages (12–13 months) [88]. Importantly, combination of low levels of the apoE4 fragment and Aβ elicit severe neuronal and behavioural deficits in transgenic mice at young ages [80]. We hypothesize that, in response to brain injury, neuronal apoE expression is induced or enhanced for purposes of repair or remodelling. However, in the context of apoE4, these events trigger proteolytic processing and fragment generation, which are detrimental to repair and remodelling and lead to neurodegeneration.

ApoE4 fragments cause tauopathy and impair mitochondrial function

We and others have shown increased phosphorylation of tau in transgenic mice expressing human apoE4 in neurons but not in mice expressing apoE4 in astrocytes [58,60,61], indicating a neuron-specific effect of apoE4 on tau phosphorylation. The increased tau phosphorylation in apoE4 transgenic mice appears to be associated with activation of ERK that can be modified by zinc concentration [62]. We have also shown that the C-terminal-truncated fragments of apoE4 enter the cytosol and cause neurodegeneration and behavioural deficits in transgenic mice [5658]. One target of these fragments is tau [56]. In vitro, the C-terminal-truncated fragments of apoE are toxic when expressed in neuronal cells, leading to tau phosphorylation and the formation of NFT-like inclusions [56,89]. In transgenic mice, the C-terminal-truncated apoE4 fragments cause tauopathy; removing tau prevents apoE4 fragments-caused neuronal and behavioural deficits in transgenic mice [88]. Thus neurotoxicity induced by the apoE4 fragments is related to tauopathy.

ApoE4 fragments also target the mitochondria of neurons, leading to mitochondrial dysfunction and neurotoxicity [59,90]. Importantly, the receptor-binding region of apoE is required for escape from the secretory pathway, and the lipid-binding region is required for mitochondrial interaction [59]. It appears that positively charged amino acids in the receptor-binding region, a feature shared among the protein translocation domains of many viral proteins [91,92], enable apoE4 fragments to translocate across membrane compartments of the secretory pathway and enter the cytosol, whereas the lipid-binding region interacts directly with the mitochondria [59]. Biophysical studies suggest that the lipid-binding domain within the C-terminal-truncated apoE4 has a less organized structure and greater exposure of the hydrophobic residues than full-length apoE4 [93,94], which might increase the interaction with mitochondrial membrane. Interestingly, almost 20 years ago, it was found that apoE avidly bound to mitochondrial ATPase [95]. In addition, small amounts of apoE have been identified in hepatocyte mitochondria [96].

ApoE4 impairs axonal transport of mitochondria in transgenic mice with neuron-specific expression of apoE4 [61]. Mitochondrial dysfunction in AD is modulated by apoE genotype [97100], and the effects are greater in apoE4 than in apoE3 carriers [101]. In both AD patients and age-matched non-demented subjects, apoE4 is associated with decreased cerebral glucose metabolism [102111], an effect that occurs decades before cognitive impairment become apparent [102,103,112] and, probably, also before significant Aβ deposition. Thus apoE4 may cause mitochondrial dysfunction at very early stages in life.

ApoE4 and its fragments impair neuronal plasticity

In the presence of lipids, apoE3 and apoE4 have markedly different effects on neurite extension [35,113119]. In both dorsal root ganglion neurons and Neuro-2a cells in culture, apoE3 plus β-VLDL (very-low-density lipoprotein) stimulate neurite extension, whereas apoE4 plus β-VLDL inhibit neurite branching and extension [35,113,114]. In addition, astrocyte-derived apoE3, but not apoE4, stimulates neurite outgrowth of rat hippocampal neurons [119]. Furthermore, apoE3-transfected Neuro-2a cells grown in medium containing β-VLDL or HDL (high-density lipoprotein) from CSF (cerebrospinal fluid) have greater neurite extension than apoE4-transfected Neuro-2a cells [120]. Finally, apoE3 stimulates, but apoE4 inhibits, neuronal sprouting in an in vitro mouse organotypic hippocampal slice culture system derived from transgenic mice expressing apoE3 or apoE4 respectively [121]. ApoE4-associated inhibition of neurite extension is probably due to its effect on microtubule stability [114] and is mediated by cell-surface lipoprotein receptors, specifically the HSPG (heparan sulfate proteoglycan)/LRP [LDL (low-density lipoprotein) receptor-related protein] pathway [35,113,120]. Specifically, apoE4 inhibits tubulin polymorization in neuronal cells, which is abolished by blocking the HSPG/LRP pathway [35,114]. Notably, apoE receptors mediate neurite outgrowth by activating the ERK pathway in primary neuronal cultures [122].

ApoE4 also impairs synaptogenesis in vivo in apoE transgenic and gene-targeted mice and in vitro in primary neuronal cultures. Dendritic spine density is lower in apoE4 transgenic and gene-targeted mice than in apoE3 mice [123,124]. In rat primary cortical neuronal cultures, addition of exogenous apoE4 or its proteolytic fragment decreases the density of dendritic spines [125]. Interestingly, rosiglitazone, an insulin sensitizer and mitochondrial activator, rescues this loss of dendritic spines [125], suggesting that the detrimental effects of apoE4 on synaptogenesis result, at least in part, from impaired mitochondrial activity.

Adult mouse neural stem cells express apoE [126] and apoE4 impairs adult hippocampal neurogenesis [126,127]. ApoE knockout mice have less hippocampal neurogenesis but more astrogenesis than wild-type mice because of decreased Noggin expression in apoE null neural stem cells [126]. In contrast, neuronal maturation in apoE4 knock-in mice is impaired owing to reduced survival and function of GABA (γ-aminobutyric acid) producing interneurons in the hilus of the hippocampus; indeed, a GABAA receptor potentiator rescues the apoE4-associated decrease in hippocampal neurogenesis [126]. Thus apoE contributes to adult hippocampal neurogenesis, and apoE4 impairs GABAergic input to newborn neurons, leading to decreased neurogenesis [126]. The impaired hippocampal neurogenesis might contribute to apoE4-associated learning and memory deficits.

Conclusion, perspective and potential therapeutic strategies

Biochemical, cell biological and transgenic animal studies have suggested several mechanisms to explain apoE4's contri-bution to the pathogenesis of AD. These include the modu-lation of the deposition and clearance of Aβ and the formation of plaques [31,33,34,76,86,128133], impairment of the antioxidative defence system [134136], dysregulation of the neuronal signalling pathways [137139], disruption of cytoskeletal structure and function [113,114,120], increased phosphorylation of tau and the formation of NFTs [56,140], impairment of glucose metabolism and mitochondrial integrity and function [59,97111] and impairment of GABAergic interneuron function and hippocampal neurogenesis [88,126]. However, the mechanisms of these apoE4-mediated effects are still poorly understood. Likewise, it is not known which of these pathophysiological effects of apoE4 is the primary effect and which are subsequent or downstream effects, or the extent to which they contribute to the pathogenesis of the dementia that characterizes AD clinically. Based on both in vitro and in vivo studies reviewed above, it is very likely that apoE4 affects AD pathogenesis by interacting with different factors through various pathways. Thus multiple molecular and cellular mechanisms should be considered when anti-AD drugs are developed based on apoE studies.

The diverse cellular pattern of expression implies multiple functions of apoE. ApoE derived from different cellular sources probably has distinct roles in both physiological and pathophysiological pathways [21,22,71]. Thus determining how apoE expression is regulated in different types of cells in the brain during development and in response to various insults should provide fundamental insights into the varied effects of apoE in neurobiology and neurodegenerative disorders, including AD. Drugs that inhibit neuronal expression of apoE4 might eliminate its downstream detrimental effects.

The Aβ-dependent effects of apoE4 on AD pathogenesis could be attenuated by developing and using drugs that inhibit apoE4-stimulated production or deposition of Aβ. Drugs could also be designed, based on Aβ-independent effects of apoE4, to inhibit the apoE cleaving enzyme that mediates apoE4 fragmentation or to block the interaction of apoE4 fragments with tau and mitochondria, thereby protecting against fragment-induced neurotoxicity. In addition, drugs capable of increasing the activity and/or numbers of mitochondria could also be beneficial for treating AD. Finally, another potential drug target is apoE4 domain interaction, which is responsible for apoE4 stimulation of Aβ production, for apoE4 potentiation of Aβ-caused lysosomal leakage, and for apoE's susceptibility to proteolytic cleavage [21,22,71]. Small molecules could be designed to disrupt domain interaction by making apoE4 structurally and functionally more like apoE3 [21,22,71]. Clearly, new hope for effective therapeutics relies on the ability of scientists to explore multiple lines of inquiry. It is certainly conceivable that there will be combination therapies, with both symptomatic drugs and those that might fundamentally alter the rate of onset and progression.


This work was supported in part by National Institutes of Heath grant [grant number P01 AG022074].


I thank Linda Turney for manuscript preparation and Stephen Ordway and Gary Howard for editorial assistance.


  • Models of Dementia: the Good, the Bad and the Future: A Biochemical Society Focused Meeting held at Robinson College, Cambridge, U.K., 15–17 December 2010. Organized and Edited by Stuart Allan (Manchester, U.K.), Christian Hölscher (University of Ulster, Coleraine, U.K.), Karen Horsburgh (Edinburgh, U.K.), Simon Lovestone (King's College London, U.K.) and Calum Sutherland (Dundee, U.K.).

Abbreviations: Aβ, amyloid β-peptide; AD, Alzheimer's disease; apo, apolipoprotein; APP, amyloid protein precursor; CNS, central nervous system; EGFP, enhanced green fluorescent protein; ERK, extracellular signal-regulated kinase; GABA, γ-aminobutyric acid; HSPG, heparan sulfate proteoglycan; LRP, low-density lipoprotein receptor-related protein; ME, multi-enhancer; NFT, neurofibrillary tangle; NSE, neuron-specific enolase; VLDL, very-low-density lipoprotein


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