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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Potential Role of Endogenous and Exogenous Ab Binding Molecules in Ab Clearance and Metabolism

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Alzheimer's disease (AD) is the leading cause of dementia in the elderly and there are currently no effective therapies for either the prevention or treatment of this disease. The last decade of AD research has been very informative in that major advances have occurred in the understanding of the genetics leading to the early-onset familial AD as well as the development of transgenic mouse models which recapitulate several important characteristics of the Alzheimer's pathology. Additionally, substantial efforts have focused on the genesis/synthesis of the Ab peptide from its precursor protein. A critical area of study that has received less attention is Ab metabolism. Only until recently have researchers begun to investigate the fate of Ab following its release from cells into different extracellular compartments. These efforts for the most part have been limited to CNS-specific proteolytic events. In this chapter we will review current studies which have begun to dissect the complex systems and molecules that work in concert to regulate Ab metabolism in both the CNS and peripheral compartments. Unraveling the mechanisms regulating Ab metabolism in vivo will likely lead to new efforts to improve AD diagnosis as well as rational drug design aimed at both preventing and treating AD.


Amyloidb (Ab) peptides are predominantly 38-43 amino acids in length and are derived from the amyloid precursor protein (APP) through a series of endoproteolytic cleavages. Abundant evidence over the last 15 years has established that the accumulation in the brain of the normally soluble Ab peptide into forms with high β-sheet content appears to be central to the pathogenesis of Alzheimer's disease (AD).1 Genetic and biochemical evidence supporting this idea is that all known mutations that cause early-onset forms of familial AD or Ab-related cerebral amyloid angiopathy (CAA) map to three genes (APP, presenilin 1 (PS1), and presenilin 2 (PS2)). Most of these mutations result in relative overproduction of Ab42, a particularly amyloidogenic form of Ab, which over time, increases the probability of Ab aggregation.1,2 Further, all individuals with Down syndrome possess three copies of APP, have increased levels of Ab,3 and all develop AD pathology by age 35.4

A major advance in AD research was the development of transgenic mice that overexpress various human mutated forms of APP genes that lead to familial AD.5,6 These animals develop age-dependent Ab accumulation and deposition in their brain. The use of these animal models has been critically important for furthering our understanding of the role of the Ab peptide in the pathogenesis of AD. Initial studies performed with the transgenic animals yielded confirmatory evidence that paralleled human genetic studies in showing that the enhanced production of the Ab peptide, more specifically Ab42, led to the pathological deposition of amyloid in brain.5 Transgenic mice over expressing multiple mutated forms of human APP and either PS1 or PS2 in various combinations result in a gene dose-dependent effect on the age of onset of amyloid deposition.7 These studies clearly demonstrate that significantly increased synthesis of the Ab peptide will ultimately result in pathology and both amyloid/Ab-dependent and -independent memory impairment.8 However, it must be remembered that the familial mutations in humans that lead to the increased synthesis of Ab account for less than 1% of the total cases of AD.

A less investigated area of study in the Ab-related area of AD has been the in vivo physiological events that occur subsequent to the synthesis of Ab. Although studying Ab metabolism post genesis is difficult, it is of paramount importance when considering that >99% of all AD cases result independently from genes known to increase Ab synthesis. This chapter will focus on recent insights into Ab metabolism using transgenic animal models of AD. We will review and discuss how Ab transport into and out of the brain as well as Ab binding proteins influence Ab metabolism in vivo.

Animal Models of AD

PDAPP mice, also referred to as APPV717F mice, were the first transgenic model reported to have significant age- and region-dependent deposition of Ab.5 These mice were generated by overexpressing a mutated APP minigene (APPV717F) in the brain under control of the platelet-derived growth factor (PDGFb) promoter. In this animal model, the majority of human mutated APP is expressed solely within the central nervous system (CNS).9 It has been shown that PDAPP animals have similar levels of brain Ab between birth and ˜ 6 months of age; however, they demonstrate marked increases in Ab levels and Ab deposition in diffuse and neuritic plaques by 8 months of age in a region-specific pattern similar to that seen in AD (deposits in the hippocampus and neocortex but little in striatum and cerebellum)10 (Fig. 11.1). Also reminiscent of the human condition is the development of neuritic plaques in these APP transgenic mice.11 Swollen, distorted neuronal processes are associated with the fibrillar Ab deposits (thioflavine S positive, i.e., amyloid plaques) (Fig. 11.2). Neuritic dystrophy is not present in areas of diffuse deposits of Ab. Other features of AD that can be seen in the various APP transgenic mouse models of AD include microglial activation, astrocytosis, evidence of oxidative damage, and some changes in neuronal cytoskeletal proteins including hyperphosphorylation of tau.12,16 However, neurofibrillary tangles are not seen and little to no neuronal cell death has been observed in any APP transgenic mouse strain, including PDAPP mice. An analysis of the depositing amyloid in aged PDAPP animals shows that the predominant Ab peptide ends in residue 42 (>90% by 16 months of age).10 Hsiao and colleagues produced a transgenic mouse model with similar phenotypic findings, Tg2576 or APPsw, wherein a prion protein (PrP) promoter was used to overexpress an APP mutation found in some Swedish families with autosomal dominant AD.6 Unlike the PDAPP model, these animals express mutated human APP both in the CNS as well as the periphery.17 In addition to possessing similar brain pathology as observed in PDAPP mice, Tg2576 mice are much more susceptible than PDAPP mice in developing cerebral amyloid angiopathy (CAA).18 Interestingly, in contrast to PDAPP mice, Tg2576 mice develop Ab deposits consisting primarily of Ab1-40 .17

Figure 1. Abundant Ab deposition can be seen in hippocampal and cortical regions in PDAPP+/+ transgenic mice.

Figure 1

Abundant Ab deposition can be seen in hippocampal and cortical regions in PDAPP+/+ transgenic mice. This coronal brain section from a 12-month-old PDAPP mouse was immunostained with a polyclonal antibody against Ab. Ab deposition is particularly prominent (more...)

Figure 2. PDAPP transgenic mice develop a neuritic dystrophy that is associated with deposited fibrillar Ab.

Figure 2

PDAPP transgenic mice develop a neuritic dystrophy that is associated with deposited fibrillar Ab. A coronal brain section from 12-month-old PDAPP+/+ mouse was stained with the de Olmos silver method to identify the neuritic dystrophy associated with (more...)

Ab Peptide Metabolism in Human

In vivo metabolism of the Ab peptide after its initial synthesis is poorly understood due to the complexity of multiple systems that work in concert to facilitate its removal from brain. However, over the past few years several important observations are beginning to yield insight into Ab's complex metabolism and clearance. Seubert and colleagues were among the first to show that a soluble form of the Ab peptide could be detected in physiological fluids (CSF and plasma).19 Subsequent studies revealed that the generation of the Ab peptide from the parent molecule, APP, occurred in almost all cell types both within the CNS and periphery.20 Neuronal cells within the CNS robustly express the APP molecule and, as a result, are thought to be the main site for Ab peptide generation. The exact function of the APP parent molecule remains speculative. Some reports indicate that it may be involved in multiple pathways (proteolytic cascades, axonal transport, neurotropic effects, protein sorting, intracellular signaling, and cellular adhesion), all of which may be nonexclusive.21,27 Similar to its parent molecule APP, the physiological function of the Ab peptide remains unknown. Indeed, the hypothesis that the Ab peptide has a biological function is quite controversial in that many believe it to be a simple by-product of APP metabolism.

The levels of soluble human Ab in the CNS are quite high as compared to the periphery (plasma) (Table 11.1). The concentration of human CSF AbTotal is ˜15 ng/ml, whereas plasma AbTotal levels are much lower at approximately 300 pg/ml.28,29 The origin of the CSF pool of soluble Ab is thought to be primarily derived from within the brain. However, the origin of peripheral plasma pool is somewhat speculative in that it is unknown how much is derived from the CNS as opposed to possible peripheral sources. Additionally, the rate of Ab syntheses in brain is quite robust and is paralleled by rapid clearance mechanisms in both the CNS and peripheral compartments.30,33 Thus, the concentrations stated above are steady state levels and represent the highly dynamic processes of synthesis and catabolism. Interestingly, the levels of CSF Ab appear in some way to be altered by the onset and progression of AD. Several studies have demonstrated that the CSF Ab42 concentrations are significantly decreased in AD patients.34,36 One possible explanation for the observed decrease in CSF Ab42 is that the deposited amyloid plaque is sequestering it. In apparent contrast to these earlier studies, Jensen and colleagues identified a significant increase in the CSF Ab42 levels early in the progression of the disease and a subsequent significant decrease in CSF Ab42 that positively correlated with the severity of dementia, a finding that the previous studies were unable to identify.37 It was hypothesized that the reduction of Ab42 in CSF that paralleled the increasing severity of dementia was most likely a result of the decreased number of neuronal cells able to produce Ab. Our recent studies in human subjects with very mild dementia likely due to AD (also termed mild cognitive impairment) reveals that CSF Ab42 is similar in these subjects vs. age-matched controls (D. Holtzman and A. Fagan, unpublished data). Since the majority of these subjects already have substantial amyloid deposition, the presence of plaques is not associated with a decrease in CSF Ab42 relative to subjects with few to no plaques. Only a few investigations have analyzed the levels of plasma Ab in AD patients vs. age-matched controls, and there does not appear to be a difference between these groups.36 Interestingly, one study suggests that cognitively normal, elderly individuals with high levels of plasma Ab may be more likely to develop dementia over a several-year period than those with lower levels.38 Further studies that analyze human subjects longitudinally both before and after the initiation of the disease will be required to fully understand and characterize the changes in CSF and plasma Ab and their relationship to AD. These studies are difficult to conduct because the onset and pathological progression of AD is thought to occur 15-20 years prior to the time of onset of even the earliest symptoms of dementia.39,40

Table 1. Ab concentrations in CSF and plasma.

Table 1

Ab concentrations in CSF and plasma.

Ab Metabolism in Wild-Type and Transgenic Mouse Models of Alzheimer's Disease

Because of the inherent limitations that arise in human studies, researchers have recently begun to utilize wild-type mice and APP transgenic mouse models of AD to investigate Ab metabolism. Initial experiments were designed to recapitulate the genetic findings whereby overexpression of the mutant forms of human APP resulted in AD-like pathology. Recent studies in transgenic animal models of AD as well as some earlier studies performed in nontransgenic animals have begun to focus on the metabolism of the Ab peptide prior to the onset of Ab deposition. Studies first performed by Zlokovic and colleagues showed that exogenously administered 125I-labeled human Ab to non-transgenic animals could be transported bidirectionally from plasma to CNS and conversely from CNS to plasma.32,41,43 Additionally, their group demonstrated that the transport was receptor mediated and could be influenced by specific Ab binding proteins.32,44 It is unknown, however, to what extent these transport mechanisms modulate the endogenous soluble pools of Ab between the CNS and periphery. Other investigators have shown that the Ab40 and Ab42 peptides are differentially transported from the CNS to the plasma/periphery. Wisniewski and colleagues demonstrated that Ab40 was rapidly transported from the CNS to plasma with a t1/2 of approximately 10 minutes, whereas the CNS to plasma clearance of the Ab42 peptide was much slower showing clearance rates similar to bulk flow of CSF to the periphery.45 If a significant quantity of endogenously produced CNS Ab has a similar fate, this metabolic pathway may be a major route of CNS Ab clearance.

Our group was interested in whether endogenously synthesized human Ab produced in the CNS is transported to and is in equilibrium with plasma Ab. For this purpose, we utilized the PDAPP transgenic mouse model where expression of the human APP transgene occurs almost exclusively within the CNS. We analyzed soluble and insoluble steady-state Ab levels in PDAPP transgenic mice that were 3 and 9 months of age.46 CSF and plasma isolated from young 3-month-old animals had steady-state concentrations of Ab that were very similar to that reported in humans (Table 11.1). Interestingly, there was a positive and highly significant correlation between the concentrations of Ab in CSF and plasma (r2 = 0.6392: p < 0.0001). Because the origin of plasma Ab in PDAPP mice is from the CNS, the data demonstrate that the Ab in the two compartments (central and peripheral) are in equilibrium. Analysis of a 9-month-old cohort, an age at which Ab deposition in brain varies from none to heavy, showed that CSF AbTotal levels were significantly lower (by 28%, Table 11.1, p = 0.01). Additionally, the observed net decrease in the overall levels of soluble Ab from 3 to 9 months of age was independent of the brain Ab load. In fact, CSF AbTotal and Ab42 levels were positively correlated with the amount of Ab load (Fig. 11.3). Animals that had high levels of Ab deposition in the cortex had correspondingly high levels of CSF Ab. Also, the presence of deposited Ab appears to negate the correlation observed between CSF and plasma Ab in that only animals lacking Ab deposits maintain a positive correlation between Ab present in the two compartments. Perhaps there is a parallel between our CSF studies in PDAPP mice with the studies of Jensen et al in humans.37 They noted a significant increase in Ab42 levels in patients with mild cognitive impairment (MCI) and a subsequent decrease in Ab levels with the progression of AD which they believe is secondary to neuronal loss/dysfunction. Most patients with MCI already have substantial AD pathology including Ab amyloid deposition.39,47 However, neuronal loss remains relatively modest at this stage of disease. Interestingly, PDAPP mice do not develop significant neuronal loss (neurodegeneration) even after high levels of deposited Ab.13 The lack of neurodegeneration may unmask the strong relationship between soluble and insoluble Ab that we have observed (i.e., positive correlation yielding increased levels detected). This interpretation is further bolstered by work from Maggio and colleagues who have shown that even so-called insoluble Ab can reversibly equilibrate with soluble Ab.48

Figure 3. CSF AbTotal andAb42 correlates with Ab deposition.

Figure 3

CSF AbTotal andAb42 correlates with Ab deposition. CSF was first isolated from 9-month-old PDAPP+/+ transgenic mice. Animals were then sacrificed and Ab load was determined in the cingulate cortex (% of area covered by Ab immunoreacivity). Strong positive (more...)

Kawarabayashi and colleagues also performed a comprehensive study of endogenous Ab metabolism in a transgenic mouse model of AD.17 They analyzed age-dependent changes in brain, CSF, and plasma Ab in Tg2576 mice. As stated above, these animals develop robust amyloid deposition that is similar to that seen in PDAPP mice and in human AD. The CSF and plasma levels of human Ab in this transgenic animal are quite high as compared to humans (Table 11.1), probably a result of the over expression of APP in both the CNS and periphery. Interestingly, they showed that levels of soluble Ab in the CSF and plasma decreased significantly during the same time frame of exponential accumulation of brain parenchyma Ab. Because their analysis focused on groups of animals at various ages as opposed to an individual animal assessment, it is unknown whether the decreased human Ab levels were solely age related or both age and plaque related. Furthermore, it may be difficult to discern meaningful relationships between CNS and plasma Ab in this animal model due predominantly to the fact that most plasma Ab in these mice is likely derived from other organs and not the CNS. It is also the case that there appears to be more limited variability in Ab deposition seen in the Tg2576 model at a given age (as compared to the PDAPP model).

Apolipoprotein E and Clusterin: In Vivo Ab Chaperone Proteins

Apolipoprotein E

Ab binding proteins undoubtedly play an important role in the metabolism of the Ab peptide. Two of the most widely investigated Ab binding proteins are apolipoprotein E (ApoE) and clusterin (also known as apolipoprotein J). ApoE is a member of the apolipoprotein family and is primarily known for its role in cholesterol metabolism. ApoE readily associates with plasma lipoproteins (chylomicrons, VLDL, LDL, and HDL) and acts as a mediator of lipoprotein particle uptake via receptor-mediated endocytosis.49 In the CNS, ApoE is synthesized locally by glial cells (astrocytes and microglia) and is found associated with HDL-like particles.50 Although the role of CNS ApoE is not completely understood, it has been hypothesized that its primary role is for lipid transport.51,52 There are three common isoforms of ApoE that arise from single amino acid interchanges at positions 112 and 158 (ApoE2, ApoE3, and ApoE4). ApoE was first discovered to potentially be an important molecule in Ab metabolism via genetics. In 1991, researchers at Duke University reported a linkage/association of late-onset AD to a region of chromosome 19. Later studies from this group identified the association of late-onset AD with the epsilon4 allele of ApoE.53 Corder et al showed that the risk of AD is increased and the probability of remaining unaffected over time decreases in an ApoE4 dose-dependent manner.54 ApoE4 is also a risk factor for CAA.55,57 ApoE4 is only partially penetrant and is considered a risk factor for the development of AD since ApoE4 carriers don't invariably develop AD, even if they live into their nineties. The fact that ApoE4 is an important AD risk factor for the most common form of AD (late-onset) has led to efforts to identify the pathophysiological role ApoE plays in AD.

Work in the early 1990s demonstrated that ApoE was associated with senile plaques in the brain parenchyma and in amyloid angiopathy.58,59 Subsequently, it was shown that amyloid burden was correlated with ApoE genotype in both AD brains53 and in patients with traumatic brain injury (increased amyloid deposition in ApoE4-positive subjects).60 Numerous in vitro biochemical studies demonstrated isoform-specific effects of ApoE on binding to the Ab peptide, altering Ab toxicity, and modulating the propensity of the Ab peptide to aggregate (for review, see refs. 61). Additionally, in vitro studies suggest that ApoE can mediate Ab clearance by lipoprotein receptor-mediated endocytosis.62,63 What was unclear, however, from these studies was whether any of these in vitro findings had physiological relevance in vivo.

In 1997 Bales, Paul and colleagues were the first to use a transgenic mouse model of AD to investigate the role of ApoE in the amyloid cascade. They generated PDAPP mice that lacked the expression of murine ApoE (PDAPP, ApoE/). Analysis of 6-month-old transgenic animals lacking ApoE expression showed a significant decrease in Ab deposition when compared to transgenic animals expressing murine ApoE. Importantly, these 6-month-old PDAPP, ApoE/ mice developed only diffuse Ab deposition and no fibrillar (thioflavine S- or Congo Red-positive) amyloid plaques. Subsequent studies have shown that PDAPP, ApoE/ mice have only diffuse plaques until very old ages (e.g., 18 months of age and greater); however, some of these animals eventually develop amyloid plaques.64 These results suggest that murine ApoE is of critical importance for the conversion of Ab to a β-sheet conformation that ultimately becomes amyloid. Utilizing a different transgenic mouse model of AD, Tg2576 or APPsw, Holtzman and colleagues confirmed and extended the results described above by demonstrating a similar ApoE-dependent phenotype for amyloid deposition as well as a dramatic reduction in the neuritic dystrophy that normally is present in the direct locale of the depositing Ab.18 The combined results from the transgenic mouse models lacking endogenous ApoE expression suggest that ApoE is critical for the development of fibrillar amyloid and its associated neuritic dystrophy.

The above studies identified a role of murine ApoE in the amyloid cascade. Our group was interested in whether the human ApoE isoforms would have a similar effect and whether an isoform-specific difference between ApoE3 and ApoE4 could be identified. We developed PDAPP transgenic mice expressing human ApoE3 or ApoE4 on the murine ApoE knock-out background (PDAPP, ApoE3 or PDAPP, ApoE4).11,65 The controls in this experiment, PDAPP and PDAPP, ApoE/ mice, developed abundant Ab deposits between 9 and 15 months of age. Similar to previous findings, the PDAPP, ApoE/ mice contained solely diffuse plaques through 15 months (non-fibrillar Ab deposits), whereas the animals expressing murine ApoE had both diffuse and fibrillar plaques. Interestingly, PDAPP, ApoE3 and PDAPP, ApoE4 mice showed a dramatic suppression of Ab deposition until ˜15 months of age or later. The Ab that ultimately deposited in these animals (>15 months of age) was both diffuse and fibrillar in nature. Additionally, we observed significantly more Ab deposition and neuritic dystrophy in ApoE4 versus ApoE3 expressing mice. Recently, we have also found that expression of ApoE2 in PDAPP mice suppressed fibrillar Ab deposition to an even greater extent than ApoE3.64 These results demonstrate that human ApoE can isoform specifically alter the amyloid deposition cascade and the neuritic toxicity associated with amyloid deposition.

Although the mechanism underlying the human ApoE effect on Ab metabolism remains speculative, the combined results above highlight a few potential mechanisms. A highly probable mechanism through which ApoE may be modulating in vivo Ab metabolism may be through “clearance”. The traditional role of ApoE in the periphery is to act as the ligand for receptor-mediated endocytosis of lipoprotein particles. It is easy to draw a parallel between the function of ApoE in the plasma to that of the CNS; however, the published literature supporting this mechanism is quite limited. In fact, to the authors' knowledge, there is only one manuscript that appears to demonstrate that ApoE-lipoprotein complexes can potentially act as a vehicle for Ab catabolism.62 Perhaps a different type of clearance mechanism is at work. Wisniewski et al investigated whether ApoE could modulate the transport of CNS-derived Ab across the blood-brain barrier (BBB) into the plasma peripheral system. No significant differences in transport across the BBB were observed for radiolabeled Ab that was injected intraventricularly in the presence of the various human ApoE isoforms.45 An important experiment that is currently being conducted in our laboratory is the analysis of all the soluble compartments in PDAPP mice for steady-state Ab levels in the presence of differing levels of human ApoE isoforms. Similar to our characterization of the PDAPP mice at multiple ages (see above), we believe that important insights into ApoE's modulation of Ab metabolism will be identified and that it is likely that ApoE does modulate Ab clearance/transport between the CNS and plasma.


The second most abundantly expressed apolipoprotein in the CNS is clusterin (also known as apolipoprotein J).66,70 CNS clusterin has several similarities to ApoE in that it too is expressed primarily by glia and is present in HDL.50,71 There are several findings that implicate clusterin as a potential player in Ab metabolism. Two of the initial observations were that clusterin was upregulated in AD brain and was found associated with deposited amyloid.72 It was subsequently found that purified clusterin can bind to soluble Ab40 with a dissociation constant characteristic of a high affinity interaction.73 Other studies have shown that clusterin may be an important regulator of soluble CNS Ab levels. Studies by Zlokovic et al have shown that Ab-clusterin complexes can be transported across the blood-brain barrier by a high-affinity receptor-mediated process involving transcytosis.42,44

Multiple in vitro studies have also highlighted a possible role of clusterin in Ab metabolism. Several laboratories have shown that clusterin prevents aggregation and polymerization of synthetic Ab in vitro.74,75 Additionally, cell culture experiments have demonstrated that Ab uptake and degradation is facilitated by the presence of clusterin.76 Oda et al showed that clusterin decreased aggregation of Ab42 and that subsequent incubation of the less aggregated material to PC12 cells significantly increased oxidative stress.74 Studies by Lambert et al demonstrated that small diffusible oligomers of Ab42 induced by the presence of clusterin were associated with increased neuronal toxicity in organotypic CNS cultures at nanomolar concentrations.77 Soluble oligomers of Ab42 were also found to be deleterious for LTP in the dentate gyrus of rat hippocampal slices78 and protofibrillar intermediates of Ab were found to induce acute electrophysiological and toxic changes to cortical neurons.79,82 Other recent studies have shown that clusterin can “solubilize” a very broad spectrum of proteins that contain exposed hydrophobic patches.79,80 Clusterin's chaperone-like activity has been attributed to a molten globule-like region located in the clusterin protein itself.81,82 While these studies suggest that clusterin/Ab interactions may be relevant to AD, whether clusterin plays a direct role in the formation of AD pathology in vivo was not clear until recently.

Our group investigated the in vivo role of clusterin in the amyloid cascade by generating PDAPP mice that lacked endogenous clusterin expression (PDAPP, Clu/).83 In contrast to the PDAPP, ApoE/ mice, no significant difference in the relative amount of depositing Ab was detected between PDAPP or PDAPP, Clu/ mice. The absence of clusterin did not influence either the age of onset of Ab deposition or the amount of Ab accumulation in PDAPP mice. Although there were no differences seen in the quantity of brain Ab, we did observe significant alterations in the structure of the depositing Ab (Fig. 11.4). Ab immunoreactivity in the PDAPP, Clu/ mice was more diffuse in appearance with fewer “compact” plaques as compared to PDAPP animals expressing endogenous clusterin. Interestingly, the prevalence of this diffuse Ab deposition was very reminiscent of the type of deposition seen in the PDAPP, ApoE/ mice. In contrast to the PDAPP, ApoE/ mice, PDAPP animals lacking clusterin expression did develop thioflavine S-positive Ab deposits (amyloid); however, there was a significant reduction in the amount and area occupied (% load) by thioflavine S-positive amyloid. Strikingly, the neuritic dystrophy surrounding amyloid deposits in PDAPP, Clu/ mice was markedly reduced with many deposits having few to no detectable dystrophic neurites. Quantitatively, there was a 10-fold reduction in dystrophic neurites in the hippocampus of PDAPP, Clu/ versus clusterin expressing mice, and a 5-fold reduction in the number of dystrophic neurites per amyloid deposit. Thus, while the presence or absence of clusterin is associated with amyloid formation, clusterin expression clearly facilitates the neuritic toxicity associated with amyloid.

Figure 4. Diffuse Ab deposition can be seen in hippocampal and cortical regions in PDAPP+/+,Clu/ transgenic mice.

Figure 4

Diffuse Ab deposition can be seen in hippocampal and cortical regions in PDAPP+/+,Clu/ transgenic mice. Coronal brain section from a 12-month-old animal was immunostained with a polyclonal antibody against Ab. Similar to PDAPP mice expressing clusterin, (more...)

The dissociation between amyloid formation and neuritic dystrophy in PDAPP, Clu/ mice implied that clusterin might be influencing a soluble “toxic” species/form of Ab during or following the process of Ab deposition. To address this possibility, we assessed the amount of carbonate-soluble brain Ab by ELISA in cortical brain homogenates under both denaturing and nondenaturing conditions. Our systematic biochemical examination of the carbonate-soluble brain extracts with a nondenaturing ELISA specific for oligomeric forms of Ab detected no significant differences between PDAPP, Clu+/+ and PDAPP, Clu/ mice. However, by using Ab ELISAs under both denaturing and nondenaturing conditions, we did identify a small but significant two-fold increase in the pool of Ab which may be monomeric in mice expressing clusterin. Although the exact meaning of this clusterin-dependent alteration of soluble Ab is unknown, these data provide direct evidence that clusterin modifies Ab metabolism and (or) structure to influence amyloid deposition and toxicity in vivo.

Exogenous Ab Binding Proteins

The preceding discussion highlighted the importance of two endogenous Ab binding proteins and sets the stage for the investigation of the effects of exogenous high-affinity Ab binding proteins on Ab metabolism in vivo. As was the case with the previous studies, the initial observations were made in vitro. In a two-chamber dialysis experiment, it was demonstrated that a high-affinity monoclonal antibody directed against the central domain of Ab, m266, was able to sequester human Ab from its endogenous CSF binding proteins and create an altered equilibrium favoring Ab passage across the dialysis membrane (25 kDa cut off).9 Although this experiment was carried out in a simple dialysis system, the result has important implications.

The data from our dialysis experiment suggested the possibility that an exogenous Ab binding molecule may be able to alter the concentration gradient and thus the equilibrium of Ab between the central (brain) and peripheral (blood) compartments in vivo and thereby favor clearance of Ab from the CNS to the periphery. The latter would promote peripheral Ab catabolism versus CNS deposition. Our first experiments to test this hypothesis were conducted in young PDAPP animals to see if the m266 antibody would alter the in vivo equilibrium between the CNS and plasma. Intravenous administration of m266 to 3-month-old PDAPP mice resulted in a dramatic accumulation of CNS-derived plasma Ab which was associated with acute changes in CNS steady-state levels of Ab. We demonstrated that all of the plasma Ab that accumulated after 24 hours following m266 administration (˜1000 fold over basal levels) was complexed with antibody. Interestingly, the rate of Ab entry into the plasma compartment following antibody administration occurred quite rapidly at ˜42 pg/ml/min. Part of this massive accumulation appears to be secondary to the antibody decreasing Ab catabolism once it reaches the plasma from the CNS. We also postulated that part of the increase was due to an increase in the net “flux” of CNS Ab to the periphery due to an antibody mediated change in Ab transport between the CNS and plasma compartments. There are at least two mechanisms by which the antibody acting as a “peripheral sink” could alter net Ab “flux”. First, by decreasing the concentration of free (unbound) plasma Ab to near zero, one would effectively block entry of Ab from the plasma into the CNS. Second, given a saturable Ab transporter, such a change in the Ab concentration gradient across the brain-blood barrier should facilitate efflux until a new equilibrium (with the free plasma Ab) is reached. Even though our “peripheral sink” hypothesis was supported by data from experiments using exogenous Ab injections into the CSF space of m266 primed wild-type mice, it still remains unclear as to how much of the plasma Ab accumulating after m266 administration is a result of increased net Ab CNS efflux or decreased peripheral catabolism of Ab (i.e., in the presence of the monoclonal antibody). We postulate that both are contributing to the massive plasma Ab concentrations observed after m266 administration to PDAPP mice.

During the same time course as the massive accumulation of plasma Ab, we observed a significant increase in CSF Ab40 and Ab42. Although the molecular mechanism underlying the increases in soluble Ab in CSF is unknown, it may signify an acute alteration in CNS Ab metabolism due to an exogenously added peripheral Ab binding protein. Perhaps the shift in equilibrium from the CNS to the periphery alters the concentration-dependent Ab catabolic processes of brain, favoring transport from the parenchyma towards the soluble compartments in CSF and plasma. Importantly, it was shown that this antibody-mediated alteration in Ab metabolism in PDAPP mice correlated with a significant decrease in plaque pathology following chronic treatment with m266.9 Bard et al showed similar effects on plaque deposition when using passive administration of different monoclonal or polyclonal antibodies against Ab.84 Our studies demonstrated that peripheral administration of an exogenous Ab binding protein (m266) could alter the in vivo metabolism of Ab in both the CNS and plasma.

Studies of peripheral administration of m266 to plaque bearing PDAPP mice further support the “flux” hypothesis. As stated previously, CSF Ab levels positively correlate with the amount of Ab deposition present in old PDAPP animals. Additionally, plasma Ab levels in these same mice did not correlate with the extent of Ab deposition.46 We wondered whether a single acute injection of m266 into 12- to 13-month-old PDAPP animals would detect Ab entering the periphery from the CNS as well as increase the flux of the soluble CNS pool of Ab to the periphery. More importantly, we wondered whether the magnitude of this flux would correlate in similar fashion to the amount of deposited brain Ab. Similar to our previous findings, we showed that plasma levels of Ab prior to m266 injection did not correlate with the amount of Ab deposited in brain.85 However, following acute m266 treatment, striking correlations between plasma Ab and the amount of deposited Ab in the brain were observed. In strong support of the flux hypothesis, we demonstrated a highly significant correlation between plasma Ab and amyloid load as early as 5 minutes post injection of m266 (Fig. 11.5). While inhibition of peripheral catabolism of Ab by m266 is likely to account for part of the increase in plasma Ab in all animals, at this 5-minute time point, it is highly unlikely that inhibition of peripheral catabolism could alone account for the correlation between plasma accumulation and plaque burden. In addition to lending support to the flux hypothesis, these experiments also suggest that administering an m266-like antibody to AD patients followed by quantitation of plasma Ab levels may represent a peripheral biological marker for detecting the presence and quantifying the amount of Ab-related AD pathology.

Figure 5. Plasma levels of Ab40 following m266 administration are highly correlated with Ab and amyloid burden in hippocampus in 12-13-month-old PDAPP mice.

Figure 5

Plasma levels of Ab40 following m266 administration are highly correlated with Ab and amyloid burden in hippocampus in 12-13-month-old PDAPP mice. Before and 5 minutes after the i.v. administration of m266 (500 mg), plasma samples were collected. Prior (more...)


Most studies utilizing transgenic animal models of AD have to date focused on the role of previously identified genes (APP and PS mutations) on Ab synthesis, deposition, and amyloid plaques. Although these studies are of great importance in verifying the mechanism of some genetic factors involved in AD, they do little to further our knowledge of Ab metabolism. This chapter focused on the importance of studying Ab metabolism in vivo. It is imperative that researchers begin to unravel the mechanisms regulating Ab metabolism in addition to Ab synthesis. This will likely lead to new efforts in rational drug design aimed at preventing and treating AD. In our own laboratories we have analyzed both the soluble and insoluble pools of Ab before and after Ab deposition has occurred. Observed correlations between CNS and plasma pools of Ab indicate a system of communication between the central and peripheral compartments and thereby demonstrate ordered processes which regulate the clearance of the Ab peptides from the brain into the circulation followed by its removal. Interestingly, studies performed with the monoclonal antibody m266 demonstrated that the rate of CNS derived Ab entry into the plasma is very rapid (˜ 42 pg/ml/min) and implies that the peripheral compartment is normally a major site for the catabolism of Ab (steady state levels are maintained between 200 to 500 pg/ml). A better understanding of the pathways by which Ab is transported between the CNS and periphery either across the blood-brain barrier as well as via interstitial fluid and CSF bulk flow pathways could provide major insights into why Ab is deposited and amyloid formation occurs in AD and CAA. Studies performed in vivo have also shown that ApoE and clusterin are important endogenous Ab binding proteins that can modulate both the final form (fibrillar or amorphous), level, and associated toxicity of the depositing Ab peptide. However, the molecular mechanisms underlying these effects remain unknown. Based upon the human genetics and supporting transgenic mouse studies, it is likely that the ApoE isoformspecific delay in deposition is being manifested through alterations in Ab clearance/metabolism. We postulate that a careful inspection and understanding of Ab metabolism in human ApoE transgenic animals will also yield novel insights and new therapeutic opportunities for intervention.


Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741–66. [PubMed: 11274343]
Sisodia SS. Alzheimer's disease: perspectives for the new millennium. J Clin Invest. 1999;104:1169–70. [PMC free article: PMC409829] [PubMed: 10545514]
Rumble B, Retalack R, Hilbich C. et al. Amyloid A4 protein and its precursors in Down's syndrome and Alzheimer's disease. N Engl J Med. 1989;320:1446–52. [PubMed: 2566117]
Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol. 1985;17:278–82. [PubMed: 3158266]
Games D, Adams D, Alessandrini R. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature. 1995;373:523–27. [PubMed: 7845465]
Hsiao K, Chapman P, Nilsen S. et al. Correlative memory deficits, Ab elevation, and amyloid plaques in transgenic mice. Science. 1996;274:99–102. [PubMed: 8810256]
Guenette SY, Tanzi RE. Progress toward valid transgenic mouse models for Alzheimer's disease. Neurobiol Aging. 1999;20:201–11. [PubMed: 10537029]
Dodart JC, Mathis C, Bales KR. et al. Does my mouse have Alzheimer's disease? Genes Brain Behav. 2002;1:142–55. [PubMed: 12884970]
De Mattos RB, Bales KR, Cummins DJ. et al. Peripheral anti-Ab antibody alters CNS and plasma Ab clearance and decreases brain Ab burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA. 2001;98:8850–55. [PMC free article: PMC37524] [PubMed: 11438712]
Johnson-Wood K, Lee M, Motter R. et al. Amyloid precursor protein processing and Ab42 deposition in a transgenic mouse model of Alzheimer's disease. Proc Natl Acad Sci USA. 1997;94:1550–55. [PMC free article: PMC19829] [PubMed: 9037091]
Holtzman DM, Bales KR, Tenkova T. et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA. 2000;97:289–297. [PMC free article: PMC16026] [PubMed: 10694577]
Irizarry MC, McNamara M, Fedorchak K. et al. APPsw transgenic mice develop agerelated Ab deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropath Exp Neurol. 1997;56:965–73. [PubMed: 9291938]
Irizarry MC, Soriano F, McNamara M. et al. Ab deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci. 1997;17:7053–59. [PubMed: 9278541]
Masliah E, Sisk A, Mallory M. et al. Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F β-amyloid precursor protein and Alzheimer's disease. J Neurosci. 1996;16:5795–811. [PubMed: 8795633]
Smith MA, Hirai K, Hsiao K. et al. Amyloid b deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem. 1998;70:2212–15. [PubMed: 9572310]
Frautschy SA, Yang F, Irizarry M. et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol. 1998;152:307–17. [PMC free article: PMC1858113] [PubMed: 9422548]
Kawarabayashi T, Younkin LH, Saido TC. et al. Age-dependent changes in brain, CSF, and plasma amyloid β protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci. 2001;21:372–81. [PubMed: 11160418]
Holtzman DM, Fagan AM, Mackey B. et al. ApoE facilitates neuritic and cerebrovascular plaque formation in the APPsw mouse model of Alzheimer's disease. Ann Neurol. 2000;47:739–47. [PubMed: 10852539]
Seubert P, Vigo-Pelfrey C, Esch F. et al. Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids. Nature. 1992;359:325–27. [PubMed: 1406936]
Selkoe DJ. Amyloid β-protein and the genetics of Alzheimer's disease. J Biol Chem. 1996;271:18295–98. [PubMed: 8756120]
Sinha S, Dovey HF, Seubert P. et al. The protease inhibitory properties of the Alzheimer's betaamyloid precursor protein. J Biol Chem. 1990;265:8983–85. [PubMed: 2111813]
Smith RP, Higuchi DA, Broze GJJ. Platelet coagulation factor XIa inhibitor, a form of Alzheimer amyloid precursor protein. Science. 1990;248:1126–28. [PubMed: 2111585]
Van Nostrand WE, Schmaier AH, Farrow JS. et al. Protease nexinII (amyloid betaprotein precursor): a platelet alphagranule protein. Science. 1990;248:745–48. [PubMed: 2110384]
Saitoh T, Sundsmo M, Roch JM. et al. Secreted form of amyloid beta protein precursor is involved in the growth regulation of fibroblasts. Cell. 1989;58:615–22. [PubMed: 2475254]
Schubert D, Jin LW, Saitoh T. et al. The regulation of amyloid beta protein precursor secretion and its modulatory role in cell adhesion. Neuron. 1989;3:689–94. [PubMed: 2518372]
Small DH, Nurcombe V, Reed G. et al. A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth. J Neurosci. 1994;14:2117–27. [PubMed: 8158260]
Kamal A, Almenar-Queralt A, LeBlanc JF. et al. Kinesin-mediated axonal transport of a membrane compartment containing betasecretase and presenilin 1 requires APP. Nature. 2001;414:643–48. [PubMed: 11740561]
Lannfelt L, Basun H, Vigo-Pelfrey C. et al. Amyloid betaprotein in cerebrospinal fluid in individuals with the Swedish Alzheimer amyloid precursor protein mutation. Neurosci Lett. 1995;199:203–206. [PubMed: 8577398]
Matsubara E, Ghiso J, Frangione B. et al. Lipoprotein-free amyloidogenic peptides in plasma are elevated in patients with sporadic Alzheimer's disease and Down's syndrome. Ann Neurol. 1999;45:537–41. [PubMed: 10211483]
Savage MJ, Trusko SP, Howland DS. et al. Turnover of amyloid betaprotein in mouse brain and acute reduction of its level by phorbol ester. J Neurosci. 1998;18:1743–52. [PubMed: 9464999]
Saido TC. Alzheimer's disease as proteolytic disorders: anabolism and catabolism of beta-amyloid. Neurobiol Aging. 1998;19:S69–S75. [PubMed: 9562472]
Shibata M, Yamada S, Kumar SR. et al. Clearance of Alzheimer's amyloidb140 peptide from brain by LDL receptor-related protein 1 at the blood-brain barrier. J Clin Invest. 2000;106:1489–99. [PMC free article: PMC387254] [PubMed: 11120756]
Iwata N, Tsubuki S, Takaki Y. et al. Metabolic regulation of brain amyloid-beta by neprilysin. Science. 2001;292:1550–52. [PubMed: 11375493]
Motter R, Vigopelfrey C, Kholodenko D. et al. Reduction of betaamyloid peptide (42) in the cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol. 1995;38:643–48. [PubMed: 7574461]
Galasko D, Chang L, Motter R. et al. High cerebrospinal fluid tau and low amyloid b42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol. 1998;55:937–45. [PubMed: 9678311]
Mehta PD, Pirttila T, Mehta SP. et al. Plasma and cerebrospinal fluid levels of amyloid b proteins 140 and 142 in Alzheimer's disease. Arch Neurol. 2000;57:100–105. [PubMed: 10634455]
Jensen M, Schroder J, Blomber M. et al. Cerebrospinal fluid Ab42 is increased early in sporadic Alzheimer's disease and declines with disease progression. Ann Neurol. 1999;45:504–11. [PubMed: 10211475]
Mayeux R, Tang MX, Jacobs DM. et al. Plasma amyloid β-peptide 142 and incipient Alzheimer's disease. Ann Neurol. 1999;46:412–16. [PubMed: 10482274]
Price JL, Morris JC. Tangles and plaques in non-demented aging and “preclinical” Alzheimer's disease. Ann Neurol. 1999;45:358–68. [PubMed: 10072051]
Yamaguchi H, Sugihara S, Ogawa A. et al. Alzheimer β amyloid deposition enhanced by ApoE epsilon 4 gene precedes neurofibrillary pathology in the frontal association cortex of nondemented senior subjects. J Neuropathol Exp Neurol. 2001;60:731–39. [PubMed: 11444802]
Zlokovic BV, Ghiso J, Mackic JB. et al. Blood-brain barrier transport of circulating Alzheimer's amyloid β Biochem Biophys Res Commun. 1993;197:1034–40. [PubMed: 8280117]
Zlokovic BV, Martel CL, Mackic JB, Matsubara E. et al. Brain uptake of circulating apolipoproteins J and E complexed to Alzheimer's amyloid β Biochem Biophys Res Commun. 1994;205:1431–37. [PubMed: 7802679]
Ghersi-Egea JF, Gorevic PD, Ghiso J. et al. Fate of cerebrospinal fluidborne amyloid β peptide: Rapid clearance into blood and appreciable accumulation by cerebral arteries. J Neurochem. 1996;67:880–83. [PubMed: 8764620]
Zlokovic BV, Martel CL, Matsubara E. et al. Glycoprotein 330/megalin: probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer's disease amyloid β at the blood-brain and blood-cerebrospinal fluid barriers. Proc Natl Acad Sci USA. 1996;93:4229–34. [PMC free article: PMC39517] [PubMed: 8633046]
Ji Y, Permanne B, Sigurdsson EM. et al. Amyloid b40/42 clearance across the blood-brain barrier following intraventricular injections in wild-type, ApoE knock-out and human ApoE3 or E4 expressing transgenic mice. J Alzheimer's Dis. 2001;3:23–30. [PubMed: 12214069]
De Mattos RB, Bales KR, Parsadanian M. et al. Plaque-associated disruption of CSF and plasma Ab equilibrium in a mouse model of Alzheimer's disease. J Neurochem. 2002;81:229–36. [PubMed: 12064470]
Morris JC, Storandt M, Miller JP. et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001;58:397–405. [PubMed: 11255443]
Esler WP, Stimson ER, Jennings JM. et al. Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism. Biochemistry. 2000;39:6288–95. [PubMed: 10828941]
Mahley RW. Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622–30. [PubMed: 3283935]
De Mattos RB, Brendza RP, Heuser JE. et al. Purification and characterization of astrocyte-secreted apolipoprotein E and J containing lipoproteins from wild-type and human ApoE transgenic mice. Neurochem Int. 2001;39:415–25. [PubMed: 11578777]
Poirer J. Apolipoprotein E in animal models of CNS injury and Alzheimer's disease. Trends Neurol Sci. 1994;17:525–30. [PubMed: 7532337]
Holtzman DM, Fagan AM. Potential role of ApoE in structural plasticity in the nervous system: Implications for diseases of the central nervous system. Trends Cardiovasc Med. 1998;8:250–55. [PubMed: 14987560]
Strittmatter WJ, Saunders AM, Schmechel D. et al. Apolipoprotein E: high avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA. 1993;90:1977–81. [PMC free article: PMC46003] [PubMed: 8446617]
Corder EH, Saunders AM, Strittmatter WJ. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late-onset families. Science. 1993;261:921–23. [PubMed: 8346443]
Schmechel DE, Saunders AM, Strittmattter WJ. et al. Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA. 1993;90:9649–53. [PMC free article: PMC47627] [PubMed: 8415756]
Greenberg SM, Rebeck GW, Vonsattel JPG. et al. Apolipoprotein E e4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995;38:254–59. [PubMed: 7654074]
Greenberg SM, Briggs ME, Hyman BT. et al. Apolipoprotein E e4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. Stroke. 1996;27:1333–37. [PubMed: 8711797]
Namba Y, Tomonaga M, Kawasaki et al. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease kuru plaque amyloid in Creutzfeldt-Jacob disease. Brain Res. 1991;541:163–66. [PubMed: 2029618]
Wisniewski T, Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett. 1992;135:235–38. [PubMed: 1625800]
Nicoll JAR, Roberts GW, Graham DI. ApoE E4 allele is associated with deposition of amyloid beta-protein following head injury. Nat Med. 1995;1:135–37. [PubMed: 7585009]
Holtzman DM. Role of ApoE/Ab interactions in the pathogenesis of Alzheimer's disease and cerebral amyloid angiopathy. J Mol Neurosci. 2001;17:147–55. [PubMed: 11816788]
Urmoneit B, Prikulis I, Wihl G. et al. Cerebrovascular smooth muscle cells internalize Alzheimer amyloid beta protein via a lipoprotein pathway: implications for cerebral amyloid angiopathy. Lab Invest. 1997;77:157–66. [PubMed: 9274858]
Yang DS, Small DH, Seydel U. et al. Apolipoprotein E promotes the binding and uptake of beta-amyloid into Chinese hamster ovary cells in an isoform-specific manner. Neuroscience. 1999;90:1217–26. [PubMed: 10338292]
Fagan AM, Watson M, Parsadanian M. et al. Human and murine apoE markedly influence Ab metabolism both prior and subsequent to plaque formation in a mouse model of Alzheimer's disease. Neurobiol Dis. 2002;9:305–318. [PubMed: 11950276]
Holtzman DM, Bales KR, Wu S. et al. In vivo expression of apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimers disease. J Clin Invest. 1999;103:R15–R21. [PMC free article: PMC408154] [PubMed: 10079115]
Roheim PS, Carey M, Forte T. et al. Apolipoproteins in human cerebrospinal fluid. Proc Natl Acad Sci USA. 1979;76:4646–49. [PMC free article: PMC411636] [PubMed: 291993]
Hochstrasser AC, James RW, Martin BM. et al. HDL particle-associated proteins in plasma and cerebrospinal fluid: identification and partial sequencing. Appl Theoret Electroph. 1988;1:73–76. [PubMed: 3154963]
May PC, Finch CE. Sulfated glycoprotein 2: new relationships of this multifunctional protein to neurodegeneration. Trends Neurol Sci. 1992;15:391–96. [PubMed: 1279864]
Aronow BJ, Lund SD, Brown TL. et al. Apolipoprotein J expression at fluidtissue interfaces: Potential role in barrier cytoprotection. Proc Natl Acad Sci USA. 1993;90:725–29. [PMC free article: PMC45738] [PubMed: 8421712]
Borghini I, Barja F, Pometta D. et al. Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid. Biochem Biophys Acta. 1995;1255:192–200. [PubMed: 7696334]
LaDu MJ, Gilligan SM, Lukens SR. et al. Nascent astrocyte particles differ from lipoproteins in CSF. J Neurochem. 1998;70:2070–81. [PubMed: 9572293]
May PC, Lampert-Etchells M, Johnson SA. et al. Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat. Neuron. 1990;5:831–39. [PubMed: 1702645]
Matsubara E, Frangione B, Ghiso J. Characterization of apolipoprotein J Alzheimer's Ab interaction. J Biol Chem. 1995;270:7563–67. [PubMed: 7706304]
Oda T, Wals P, Osterburg HH. et al. Clusterin (ApoJ) alters the aggregation of amyloid bpeptide (Ab142) and forms slowly sedimenting Ab complexes that cause oxidative stress. Exp Neurol. 1995;136:22–31. [PubMed: 7589331]
Matsubara E, Soto C, Governale S. et al. Apolipoprotein J and Alzheimer's amyloid beta solubility. Biochem J. 1996;316:671–79. [PMC free article: PMC1217400] [PubMed: 8687416]
Hammad SM, Ranganathan S, Loukinova E. et al. Interaction of apolipoprotein J amyloid betapeptide complex with low density lipoprotein receptor-related protein2/megalin. A mechanisms to prevent pathological accumulation of amyloid beta peptide. J Biol Chem. 1997;272:18644–49. [PubMed: 9228033]
Lambert MP, Barlow AK, Chromy BA. et al. Diffusible, nonfibrillar ligands derived from Ab142 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA. 1998;95:6448–53. [PMC free article: PMC27787] [PubMed: 9600986]
Wang HW, Pasternak JF, Kuo H. et al. Soluble oligomers of beta amyloid (142) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res. 2002;924:133–140. [PubMed: 11750898]
Humphreys DT, Carver JA, Easterbrook-Smith SB. et al. Clusterin has chaperone-like activity similar to that of small heat shock proteins. J Biol Chem. 1999;274:6875–81. [PubMed: 10066740]
Poon S, Easterbrook-Smith SB, Rybchyn MS. et al. Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry. 2000;39:15953–60. [PubMed: 11123922]
Bailey RW, Dunker AK, Brown CJ. et al. Apolipoprotein J expression at fluid-tissue interfaces: Potential role in barrier cytoprotection. Proc Natl Acad Sci USA. 2001;90:725–29. [PMC free article: PMC45738] [PubMed: 8421712]
Dunker AK, Lawson JD, Brown CJ. et al. Intrinsically disordered protein. J Mol Graphics Model. 2001;19:265–9. [PubMed: 11381529]
De Mattos RB, O'Dell MA, Parsadanian M. et al. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA. 2002;99:10843–48. [PMC free article: PMC125060] [PubMed: 12145324]
Bard F, Cannon C, Barbour R. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer's disease. Nat Med. 2000;6:916–19. [PubMed: 10932230]
De Mattos RB, Bales K, Cummins DJ. et al. Brain to plasma amyloid-beta efflux: A measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science. 2002;295:2264–67. [PubMed: 11910111]
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