. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature. 2005 Oct 6;437(7060):906-10. PubMed.


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  1. The newly proposed role for ApoE in lipid antigen presentation reported by van den Elzen et al. casts a new and interesting light on the results published by Hirsch-Reinshagen et al., Koldamova et al., and Wahrle et al.. Van den Elzen et al. show that ApoE binds directly to lipid antigens and delivers them into CD1-bearing dendritic cells by receptor-mediated endocytosis much more efficiently than macropinocytosis does. This process eventually leads to the production of interferon-Aγ and other cytokines. The results in the paper point to the presentation of foreign lipids (such as bacterial pathogens), whose role in the pathogenesis of AD is not well established [Editor’s note: see ARF Live Discussion ]. However, the presentation of endogenous lipid antigens such as sulfatide could be potentially very important in activating microglia and astroglia as well, especially in the execution of their Aβ-clearing capacity. The sphingolipid sulfatide is the main constituent of mammalian brain lipids. In CNS it is transported by ApoE-containing lipoprotein particles and was found to be decreased in AD patients (3). Previous data support a role for ApoE as an immunomodulatory agent affecting both the innate and adaptive immune responses. For example, ApoE modulates the CNS inflammatory response by down-regulating glial secretion of inflammatory cytokines and neurotoxic mediators such as nitric oxide, which is important in exacerbating neurodegeneration. Another study demonstrated that ApoE deficiency results in impaired clearance of apoptotic cell remnants (1). A regulatory role of ABCA1 in the engulfment of apoptotic bodies was suggested about 10 years ago, at the time its cDNA was initially cloned, and now we know that such a role is being mediated, at least in part, by ApoE (2).

    Although the genetic association of ApoE and Alzheimer disease has been known for more than 10 years now, and ApoE4 is indeed the only proven independent risk factor, these recent studies, including the papers in JBC (5,12) are helping to explain why ApoE is essential and how it works to prevent or facilitate Aβ aggregation, amyloid deposition, and clearance. More importantly, the fact that ABCA1 controls ApoE lipidation status and thus its proper function in the brain opens completely new directions for drug design and therapeutic interventions in Alzheimer disease (7). In this respect, it appears that the availability of brain cholesterol and phospholipids to different carriers is critical for their function, and maintaining the appropriate distribution of brain lipids rather than inhibition of their synthesis may have a protective or even therapeutic effect in AD.

    View all comments by Iliya Lefterov
  2. In our study, we used APP23 transgenic mice in which human familial Swedish AD mutant is expressed only in neurons, and we demonstrate that targeted disruption of ABCA1 transporter increases amyloid deposition. The effect was manifested by an increased level of Aβ as well as thioflavin S-positive plaques in brain parenchyma. Moreover, the lack of ABCA1 considerably increased the level of cerebral amyloid angiopathy (CAA) in APP23/ABCA1-/- mice. The fact that the elevation of the fraction of insoluble Aβ in old APP23/ABCA1-/- mice was accompanied by no change in soluble Aβ in young APP23/ABCA1-/- mice, and no difference in APP processing supports a conclusion that ABCA1 has a bigger impact on amyloid deposition than on amyloid production. Our data are in agreement with studies from Holtzman’s (12) and Wellington’s (5) groups. They demonstrated that ABCA1 deficiency in transgenic mice expressing human APP, harboring different FAD mutations and under the control of different promoters, increases amyloid deposition. In PDAPP mice (12) there was a considerable increase in insoluble Aβ level and a trend toward an increase of Aβ and thioflavin S-positive deposits. In the TgSwDI/B transgenic AD model (5), a substantial increase in thioflavin S load in hippocampus and thalamus was found, although not paralleled by changes in Aβ levels as measured by ELISA. In the same study, the Wellington group used a second APP transgenic model, APP/PS, and found no change in amyloid deposition. All three studies demonstrate a considerable increase of CAA. It is remarkable that in the three studies the elevation in parenchymal amyloid and CAA was accompanied by a dramatic decrease in soluble ApoE levels in the brain. Some of the results reported in the three papers, however, do not overlap:

    1. Whereas we and Wahrle et al. (12) found a considerable increase in insoluble Aβ peptides in APP23 and PDAPP mice, Hirsch-Reinshagen et al. (5) reported no change in insoluble Aβ fraction in APP/PS1 or in TgSwDI/B transgenic mice. This discrepancy could be explained by the expression of APP transgenes producing Aβ species with different ability to aggregate or propensity for clearance. In APP/PS1 and Tg-SwDI/B mice, the expression of PS1 or Swedish, Dutch, and Iowa triple-mutant APP increases the proportion of more hydrophobic Aβ peptides (5), which are known to aggregate faster and undergo inefficient clearance compared to Aβ40 peptide.

    2. While ABCA1 deficiency in APP23 and Tg-SwDI/B (5) caused an increase in amyloid plaques and a trend towards increase in PDAPP mice (12), Hirsch-Reinshagen et al. did not find a difference in amyloid deposition in APP/PS1 mice (5), which were examined at the more advanced age in terms of AD pathology. One explanation could be a role for ABCA1 in the initial period of aggregation and accumulation of amyloid.

    The main conclusion from these three studies (Hirsch-Reinshagen et al., Koldamova et al., and Wahrle et al.) is that there is a negative correlation between amyloid load and the level of soluble, properly lipidated ApoE in the brain. Two contrasting roles for ApoE on amyloid deposition have been proposed: one promoting amyloid deposition and another mediating Aβ clearance. The first is supported by numerous in vivo data demonstrating that in transgenic APP mice with genetically disrupted endogenous mouse ApoE, fibrillar thioflavin S-positive Aβ deposits in brain parenchyma and vasculature are virtually missing. The second one is supported by in vitro and in vivo data demonstrating that ApoE has an important role in Aβ clearance across blood-brain barrier (BBB) and by astrocytes, a process mediated primarily via LDL receptors LRP1 and LRP2 (6,9). The three present JBC papers help to explain these seemingly contradictory effects of ApoE on amyloid aggregation and clearance by the differential roles of its lipid-rich and lipid-poor states. First, ApoE binding to various LDL receptors depends on its lipidation status: Lipid-poor ApoE is a weak ligand for LRP and LDL receptors, and this could explain the decreased Aβ clearance in ABCA1-/- mice. Insufficient and poorly lipidated ApoE in brain decreases Aβ clearance and degradation, and its retention in CNS will consequently increase amyloid deposition. Second, it was demonstrated that lipid-poor ApoE is more effective than lipid-rich ApoE in promoting Aβ aggregation (8). Previous work by Holtzman’s and Wellington’s groups demonstrated that ApoE in CSF of ABCA1-/- mice, as well as ApoE secreted in the conditioned media of ABCA1-/- astrocytes, is in a lipid-poor state (4,11). Moreover, it is obvious that, as in the periphery of ABCA1-/- mice or Tangier patients, poorly lipidated ApoA-I and ApoE proteins in the brain are unstable and are subjected to fast catabolism, explaining their decreased level.

    View all comments by Iliya Lefterov
  3. Comment on the Wahrle et al., Koldamova et al., and Hirsh-Reinshagen et al. papers
    Our laboratory and the laboratories of Iliya Lefterov and Cheryl Wellington reported on the effects of ABCA1 deletion on deposition of Aβ in four different mouse models of Alzheimer disease (AD). As shown in previous work from our lab and that of Wellington’s, deletion of ABCA1 leads to poor lipidation of ApoE and large reductions in ApoE levels in the plasma, cerebrospinal fluid, and brain parenchyma. Since mouse models of AD that have reduced or no expression of mouse ApoE develop significantly less Aβ deposition and also greatly reduced deposition of thioflavin S-positive Aβ, we expected that the decreased levels of ApoE present in ABCA1 knockout mice would lead to less Aβ-related pathology in ABCA1-/- mice bred to mouse models of AD. Contrary to this hypothesis, all three laboratories found that deletion of ABCA1 either has no effect or even increases Aβ-related pathology in four different mouse models of AD. These results indicate that the poorly lipidated ApoE produced by ABCA1-/- mice may increase Aβ fibrillogenesis The papers come to similar conclusions with different mouse models and different methods, which strengthens and supports the finding of all three papers.

    The Holtzman laboratory found that PDAPP (APPV717F) mice crossed onto an ABCA1-/- background have significantly more Aβ deposited in their brains and have a higher prevalence of cerebral amyloid angiopathy (CAA). There were no differences in APP processing in young PDAPP, ABCA1-/- mice that would account for the higher level of Aβ deposition. Additionally, the PDAPP, ABCA1-/- mice accumulated insoluble ApoE in plaques at a higher rate than PDAPP, ABCA1+/+ mice, suggesting that lipid-poor ApoE is not only more amyloidogenic but also that it binds to fibrillar Aβ. Using the APP23 (APPK670N, M671L) mouse model, the Lefterov group also showed that deletion of ABCA1 resulted in increased deposition of total and fibrillar (thioflavine S-positive) Aβ, which was not a result of altered APP processing. The Lefterov laboratory found significantly higher amounts of CAA and associated microhemorrhage in APP23, ABCA1-/- mice than APP23, ABCA1+/+ mice. The Wellington laboratory bred ABCA1-/- mice to two other mouse models: Tg-SwDI/B (APPK670N, M671L, E693Q, D694N) and APP/PS1 (APPK670N, M671L, PS1 DeltaE9). They did not see significant changes in soluble or insoluble Aβ in brain. However, this lack of an effect on Aβ deposition is still interesting given that the large decreases in ApoE levels in ABCA1-/- mice were expected to lead to large decreases in Aβ deposition. The Wellington group also noted increased insoluble ApoE in the ABCA1-/-, TgSwDI/B and ABCA1-/-, APP/PS1 mice compared to their respective ABCA1+/+ controls once plaques developed, again suggesting that the lipid-poor state of ApoE in ABCA1-/- mice may increase the fibrillogenesis of Aβ. Overall, the findings these papers suggest that modifying the lipidation state of ApoE in the brain may influence AD pathogenesis and be a potential treatment target.

    View all comments by Suzanne Wahrle
  4. Three papers by Hirsch-Reinshagen et al., Koldamova et al., and Wahrle et al. (1-3) have now investigated the role of ABCA1 in Alzheimer disease neuropathology in vivo. Two very important findings were common to all three groups, demonstrating that these effects are robust and hold true across specific strains and particular animal models. Firstly, all groups corroborated prior findings of significantly reduced ApoE levels in the brains of ABCA1-deficient mice. Secondly, and contrary to all expectations, the ABCA1-mediated reduction of ApoE levels did not decrease amyloid formation, as would have been expected from previous studies showing that ApoE levels determine the extent of amyloid deposition in vivo.

    All three groups reported that ABCA1 deficiency led to an 80 percent reduction in soluble ApoE levels, independent of mouse strain or AD model. Impaired ApoE secretion from both primary astrocytes and microglia has been shown to occur in ABCA1-deficient cells (4) and might partially explain this phenomenon. Additionally, increased catabolism of the poorly lipidated ApoE particles present in ABCA1-deficient brains is likely to occur, as has been demonstrated for peripheral ApoA1 in Tangier disease (5). Given that ABCA1 is required to maintain normal brain ApoE levels, and because ApoE plays a key role in AD pathogenesis, further studies elucidating the exact mechanisms by which ABCA1 participates in brain ApoE metabolism are warranted.

    The other common result to all papers is that despite a large decrease in soluble ApoE levels, no reduction in amyloid burden was observed in any of the four AD models tested. This suggests that ApoE lipidation status, which is reduced in ABCA1-deficient animals, is a crucial regulator of amyloid formation. In addition, different Aβ species and their specific deposition pattern did not influence the amyloidogenic effect of lipid-poor ApoE. ABCA1-deficient mice on either Tg-SwD/I, PDAPP, or APP23 background had increased amyloid burdens compared to their wild-type controls, suggesting that neither their specific Aβ species nor its deposition pattern (predominantly vascular in the Tg-SwD/I and parenchymal in the PDAPP and APP23 models) modulates amyloid formation in the presence of poorly lipidated ApoE. Together, all three papers demonstrate that low levels of poorly lipidated ApoE support at least as much amyloid deposition as wild-type levels of normally lipidated ApoE. How lipidation of ApoE contributes to the process of Aβ fibrillization, deposition, and clearance remains to be fully elucidated.

    Although the most important findings were indeed corroborated by all groups, some differences were present and may be primarily related to methodological variables and time of analysis. Firstly, Koldamova et al. report an increase in amyloid and Aβ burden in APP23 mice that lacked ABCA1. Wahrle et al. reported a significant increase in guanidine-extractable Aβ load, but did not detect a significant change in amyloid burden. Hirsch-Reinshagen et al. report an increase in amyloid load in the Tg-SwD/I model but no detectable change in amyloid load in APP/PS1 mice that lacked ABCA1, and no change in guanidine-extractable Aβ levels in either model. Even though all groups saw no reduction in amyloid deposition despite a large decrease in ApoE levels, the differences in amyloid and Aβ load between wild-type and ABCA1-deficient mice may have been dependent on the stage of progression of AD. For example, in the APP/PS1 model, where severe pathology was present at the moment of analysis, no differences were observed in amyloid burden or guanidine-extractable Aβ levels between wild-type and ABCA1-deficient mice. In all other three models, analyzed at relatively earlier stages of disease progression, ABCA1-deficient animals did show an increase in amyloid burden when compared to wild-type controls. Further studies might clarify whether the role of ApoE in amyloid formation is most important during the initial stages of Aβ fibrillization, or whether other differences among the models tested may account for the differences in Aβ compared to amyloid burden.

    A second important difference among the three studies relates to the report of a shift in ApoE distribution from a soluble to an insoluble pool. Wahrle et al. and Hirsch-Reisnhagen et al. showed an increase in guanidine-extractable pool of ApoE in ABCA1-deficient brains compared to controls. Koldamova et al., using formic acid extractions, did not observe such a phenomenon. Again, it is unclear whether this discrepancy is only of methodological nature or if singularities of the mouse model used by Koldamova et al. are responsible for this. The mechanisms underlying the shift of ApoE into an insoluble form are probably closely related to the increased amyloidogenicity of lipid-poor ApoE and are therefore an interesting subject for further studies.

    View all comments by Cheryl Wellington

This paper appears in the following:


  1. ABCA1 Loss Lowers ApoE, Not Amyloid; New ApoE Immunology