Past Webinar

The Role of ApoE in Alzheimer's Disease: An Alternative View

Tuesday, December 11, 2001 at 12:00 AM US EST

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Introduction

Keith Crutcher led this live discussion on 11 December 2001. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

Live discussion held on 11 December 2001.

Participants: Keith Crutcher, Nico Stanculescu, June Kinoshita, Bruce Teter, Marcos Marques, Alexei Koudinov, Jacob Raber, Bill Rebeck, Steve Rockwood.

Note:The transcript has been edited for clarity and accuracy.

June: Greetings everyone, why don't we begin today's discussion. Keith, would you like to make an opening statement?

Keith Crutcher: I think I have posted a fairly complete summary of the main idea, which really boils down to the notion that apoE is likely to be a much more important contributor to AD than just a contributor to amyloid deposition (for which there is already good evidence). I think the most important feature of the hypothesis is that it potentially provides an explanation for both plaque and tangle pathology as well as neuronal degeneration.

June: All of you others should be thinking up great questions to ask!

Keith Crutcher: I should note that my interest in apoE arose partly from my disappointment with amyloid as an explanatory mechanism. However, I don't think this is the time to point out the many weaknesses (IMHO) of the amyloid hypothesis.

Alexei Koudinov: The isoform-specific role of ApoE in defining aggregation properties of Ab may have to do with initial ignoring of the major function of apoE, namely its participation in lipid-, particularly cholesterol-, metabolism

June: What's the most damning evidence AGAINST the amyloid hypothesis, in your view?

Keith Crutcher: For one thing, I think the epidemiological evidence implicates apoE much more than AbPP.

Jacob Raber: We definitely see cognitive impairments in hAbPP-transgenic mice before they develop plaques, but ADDLs could contribute to the cognitive deficits.

Keith Crutcher: It is more helpful to think of criticisms of the apoE hypothesis.

Alexei Koudinov: Let's talk creatively.

June: So what is wrong with the dominant ApoE hypothesis, apart from its convergence on Ab as the disease mechanism?

Keith Crutcher: I'm not sure I know what the dominant apoE hypothesis is...effect on amyloid deposition? There seems to be an emerging consensus that amyloid deposition is an insufficient basis for understanding AD. I also think it is important to keep in mind that apoE may be contributing to AD regardless of isoform.

Alexei Koudinov: I would recommend the following references on this point: Joseph et al. 2001; Mesulam, 1999; Lue et al, 1999; Koudinov et al, 2001.) Also, a recent paper by a Scottish group (White, et al. 2001) points to importance of both apoE and apoJ in lipid redistribution under neuronal tissue repair.

Keith Crutcher: Yes, I think the idea of relative contributions to repair is still reasonable. But the dominant negative effect of E4 would suggest to me that this is not a sufficient explanation.

Alexei Koudinov: We discuss several possibilities for the role of apolipoproteins in our recent article (Koudinov et al, 2001b.)

Keith Crutcher: Yes, Alexei, and I wonder which of those possibilities you favor and why.

Alexei Koudinov: I mean not only apoE isoform differences, but also the pathways apoE could be involved with in the brain. They are those discussed by many groups. For example, cholesterol redistribution via brain tissue lipoproteins and mediated by apolipoproteins and lipoprotein receptors, ApoE's importance for synaptic plasticity, lipoprotein cholesterol removal from the brain and CSF to periphery. See (Shibata et al. 2000, Demeester et al. 2000, Rebeck et al. 1998, Koudinov et al., 2002.)

Marcos Marques: What did you think of the recent Science paper by Frank Pfrieger's group (see ARF story) claiming that cholesterol/apoE is involved in synaptic development?

Alexei Koudinov: Regarding this article, there are several background observations that are critical to it. I recommend these as further reading: (Teter et al., 1999; Fan et al. 2002; Champagne et al., Soc. Neurosci Abstract 26, 1546; Matthies et al. 1997).

Keith Crutcher: I think the evidence for cholesterol involvement in synaptogenesis is very strong, but I don't think this calls into question the possibility of apoE contributing to pathology. I think one issue is that we still don't know enough about what apoE is doing "normally".

Bill Rebeck: Do we think apoE has a job "normally", or that it only shows up during some kind of damage?

Alexei Koudinov: I think there is a normal job, see references above.

Keith Crutcher: Hi Bill, good question. I think apoE does have "normal" functions and, in fact, my suspicion is that what is happening in AD is a reflection of its normal function.

Bill Rebeck: Which is? Cholesterol delivery? Don't cells make enough of their own?

Keith Crutcher: One possibility is plasticity, as others have suggested. But plasticity involves both the generation and the removal of connections.

Alexei Koudinov: It must be to ensure synaptic plasticity structure-functional rearrangements (details in Koudinov & Koudinova, 2001). Both synthesis and distribution seems critical. Several studies point to this, see references above.

Keith Crutcher: Alexei, yes, I agree that both synthesis and distribution are relevant.I don't think cholesterol delivery is its only role, but I think the idea that apoE's interaction with lipids is critical to understanding its metabolism is highly relevant.

Bill Rebeck: Is there any evidence that apoE4 people have worse plasticity, outside of AD?

Keith Crutcher: Another good question. I don't know of direct data on this, nor how to really acquire it. Arendt's data in AD brains (Arendt et al, 1997) suggests this possibility but I don't know any other data.

Marcos Marques: Bill, I think there is, like the pugilistc dementia and neuropathology in E4 AIDS patients. (Corder et al., 1998; Dunlop et al, 1997).

Keith Crutcher: Marcos, but this would assume that the relevant variable is plasticity, for which there is no direct evidence, I don't think.

Alexei Koudinov: As for apoE4 isoforms, I recall Jude Poirier's group presenting a poster on behavioral analysis in mice in San Diego. (Find abstract.)

Keith Crutcher: Jude is a strong proponent of the idea that apoE is good, regardless of isoform, and we just need to increase apoE.

Bill Rebeck: What about the stroke data? The epidemiology about apE isoforms and stroke is weak, I think, but is there any neuropathology?

Bruce Teter: Plasticity outside of AD has not been examined directly by synaptic markers, although accumulating evidence for preclinical manifestations of the presence of E4 continue to show up (in brain imaging).

Keith Crutcher: Having worked in the plasticity field as well, I am also skeptical of the idea that just increasing plasticity is going to improve things.

Marcos Marques: I agree there is no direct evidence of worse plasticity being the major player in AD. However, I think what I cited above supports a worse plasticity in apoE4 people, potentially explaining why apoE4 people have higher cognitive impairment or poorer neuronal survival under "stress/disease". My assumption here is that apoE has a normal neurotoxicity role involved in plasticity, but the aging process or stress (such as head injury/virus infection) could lead to overly active neurotoxicity, consequently resulting in AD. In that regard the higher toxicity of the E4 isoform over that of E3 could explain its genetic risk and at the same time explain why E3 people still could get AD.

Alexei Koudinov: Joachim Herz discusses a possible signaling function for apoE LRP receptor in several articles. (Herz, 2001; see also our commentary to it, at Koudinov and Koudinova, 2001c). And there is a Japanese article on detailed characterization of apoE knockins in mice, (Hamanaka et al., 2000.) We also refer to this in our articles "Drs. Koudinov Alzheimer Bibliography."

Keith Crutcher: I think the evidence for signaling effects is especially interesting and relevant.

Keith Crutcher: I also think the evidence for a role for apoE as an anti-infective agent needs to be explored.

June: Are you referring to Ruth Itzhaki's findings?

Keith Crutcher: June, I was thinking of her data but also the data coming from apoE KO mice, which are much more susceptible to infections.

Keith Crutcher: Like in any multifactorial disease, what needs to be defined are the pleiotropic effects of specific genes.

Keith Crutcher: I think the apoE field has been dominated by this cholesterol transport hypothesis to the exclusion of other possible roles of this protein.

Bill Rebeck: I think we need to start organizing the functions of apoE into some coherent patterns: delivery of lipids, activation of specific receptor-mediated processes. It's too confusing right now.

Keith Crutcher: I agree, Bill.

Alexei Koudinov: You are right, Bill

Bill Rebeck: I also think the knockout mice are difficult to interpret if apoE has roles in development.

Keith Crutcher: Bill, yes, that is a good point, as is the case for all transgenic data.

Alexei Koudinov: I agree.

Jacob Raber: Although it may give you some hints regarding what to look for when apoE is present.

Keith Crutcher: Nevertheless, the observations are intriguing and probably relate to well-known interactions with heparan sulfate proteoglycans, which serve as receptors for various infective agents.

June: Re: ApoE knockouts, it is time to do conditional knockouts! Anyone working on this?

Keith Crutcher: June, I think some groups are working on conditional knockouts. I also think that the epidemiology for apoE effects in humans is relatively unexplored for many putative roles of apoE.

Alexei Koudinov: I am not aware. And what about knocking out the function of a selected brain area, as done in (Riedel et al., 1999)?

June: Keith and I have talked about constructing a pathway diagram to depict all of the reported possible mechanisms. I'm wondering if there is some way to construct such a pathway diagram through a collective effort.

Alexei Koudinov: Good idea

Bruce Teter: Pathway diagram- wonderful idea, let's set up a common site, start with a basic structure, and have everyone be able to add to it.

Bill Rebeck: I love the idea of a pathway chart, but can it be one where every thought does not get put in until at least several people agree on it? Too many pathways just puts off research....

Keith Crutcher: Bill, yes I think that is a potential problem. Maybe a pathway could be indicated with links to supporters. (In my case, the neurotoxic hypothesis may only have one link!)

June: Each pathway needs to be annotated and have a "weight" assigned to it that represents the strength of the evidence.

Keith Crutcher: I also would like to see a clear distinction made between levels of analysis for such a diagram.

Bruce Teter: Any ideas for how this could work - web site, graphics, moderator?

Keith Crutcher: ARF is the most logical location for this.

June: I can set up a pathway site on the Alzheimer Research Forum web site. It won't be interactive (not unless I invest a huge amount in software development), but people can comment, and I can make changes to the diagram.

Alexei Koudinov: By the way how many hits does ARF collect per week?

June: Alexei, we get around 14,000 visits per week. I estimate that around 60-70 percent are researchers.

Alexei Koudinov: Great

Keith Crutcher: I think the amyloid field would benefit from such a diagram as well.

June: I've thought about that as well. But that's an even bigger challenge. ApoE might provide a nice test bed for the system.

Keith Crutcher: Well, apoE is more important anyway :-)

Marcos Marques: Interesting too, is how people will evolve in their acceptance of new ideas, like for example the neurotoxic role for apoE, which is part of today's discussion.

Bill Rebeck: I know of two or three other groups who talk about apoE4 toxicity. Including me.

Keith Crutcher: I think indicating the weight of evidence might be difficult but indicating the amount of support from the scientific community could be illuminating in many ways. Well, we have at least two or three links to the neurotoxic hypothesis! And I know that Mary Jo LaDu, who was an early contributor to the idea, hasn't completely abandoned it (even though she is focused on Ab-derived diffusible ligands now.)

Alexei Koudinov: What is your opinion, Marcos?

Marcos Marques: Alex/Bill, it is comforting that when confronted with experimental evidence, people can change their opinion, maybe we have some examples in the room :-)

Alexei Koudinov: By the way, another cross of apoE and Ab could be through their competition for lipoprotein receptors, as they both bind to it and both are players on lipid metabolism (Winkler et al. 1999; Zlokovic et al., 1996; Koudinov et al., 1998).

Keith Crutcher: Alexei, I agree that the interaction with receptors is likely to be very important.

June: Regarding the neurotoxicity hypothesis, what are the most compelling data to support it?

Keith Crutcher: I tried to summarize the most relevant data in my overview. I think both in vitro and in vivo data are consistent with the idea that apoE4 has greater neurotoxicity.

Bill Rebeck: I like the data linking apoE to changes in intracellular calcium and then downstream effects (Ohkubo et al., 2001.)

Alexei Koudinov: Another good point

Keith Crutcher: Yes, we had also seen effects of truncated apoE on intracellular calcium that seemed to correlate with neurotoxicity (Tolar et al. 1999). Neurotoxicity! The Japanese group provided quite impressive evidence for a role of intracellular signaling pathways.

Bill Rebeck: I have been trying to argue that apoE normally has short-term effects but then is cleared, but in AD it gets stuck on those plaques for a long time, having chronic effects.

Keith Crutcher: Bill, yes I think this idea of apoE hanging around and persistently activating receptors is very nice.

Alexei Koudinov: We discuss in Koudinov & Koudinova, 2001, that during the synaptic efficacy amplification, apoE may act through lipoprotein receptors in a short-time period of the long-term potentiation onset.

Marcos Marques: I think one interesting aspect about a putative apoE isoform trans-signal effect is that it may be related not only to differential isoform receptor affinity (as observed in neuronal cell lines (Ji et al., 1998) but, more importantly, to a differential apoE isoform intracellular fate, particularly in real neurons (Dekroon et al., 2001, Neurobiol disease). To complicate matters, the specific lipids that can be associated with apoE can interfere with apoE proteolysis (Bradley et al., 1984). I speculate that apoE proteolysis could be involved in trans-signal effects of apoE via a feedback effect that depends on isoform specificity and/or lipid association. Thus, the LRP/NMDA trans-signal effect demonstrated in Bill Rebeck's lab [Bacskai et al., 2000] should also be observed for apoE, but I predict that this is related to the generation of 22 kDa apoE, which shows calcium influx mediated by LRP/NMDA as we previously demonstrated (Tolar, 1999).

Keith Crutcher: In the Tolar et al. paper, we had also found a linkage between the truncated-apoE effect and NMDA receptors, something that really surprised us, but we were happy to find that Bill's group found similar things.

Bill Rebeck: Did anyone see that data from Ulrike Beisiegel talking about apoE recycling after endocytosis? Another mechanism that may differ between isoforms. (Heeren J, 2001).

Keith Crutcher: Yes, the Beisiegl data point to another possible mechanism.

Keith Crutcher: Sounds like we don't have strong skeptics here.

Alexei Koudinov: ... so, the change in apoE recycling can make a very important difference. It also may change the recycling of cholesterol that apoE normally mediates.

Marcos Marques: The isoform-differential intracellular fate of apoE could also be related back to intracellular apoE proteolysis and its "potential" neurotoxic effect.

Bill Rebeck: If you buy that apoE receptors have signaling functions, it's not a large step to apoE sometimes having toxic effects. The question is when and how strong.

Steve Rockwood: {enters}

June: Hi Steve!

Steve Rockwood: Hi, June.

Alexei Koudinov: I also mean apoE receptors as a way to deliver lipoprotein cholesterol for structural, and likely immediate, plasticity needs.

Keith Crutcher: Yes, that is one of the points I tried to make. The fact that apoE can activate intracellular pathways opens up a whole new vista on possible effects on neurons. The fact that it seems to be linked to NMDA, with its well-known excitotoxic links, is especially intriguing.

Bill Rebeck: I think the presence of excess cholesterol signals nearby cells to branch out. Those cells need the cholesterol and the signal.

Alexei Koudinov: ... cholesterol to get integrated structurally in new dendritic processes. Thanks for bringing up this issue...

Keith Crutcher: One relatively unexplored avenue is the extent to which lipids might modify these signaling effects.

Bill Rebeck: True, Keith. It's just hard working with those lipids.

Keith Crutcher: Yes, indeed, but maybe that is where some of the action is? Bill, what kind of signal do you envision for this?

Bill Rebeck: I think the first step is those proteins that bind the cytoplasmic tail of apoE recepotors. Disabled, Fe65, etc.

Keith Crutcher: Do you think these proteins will serve as linkages to the NMDA receptor as well?

Bill Rebeck: Yes, I think the NMDA linkage is real. I think LRP and NMDA are both right there in the synapse.

Alexei Koudinov: …as supported by highest expression of lipoprotein receptors in pyramidal cell layers of CA1 and the granule cells of the dentate gyrus in the hippocampus.

Keith Crutcher: Bill...I agree. This is probably a very important direction to pursue.

Bill Rebeck: Maybe linking activity to plasticity.

June: Keith, have the proteases that cleave apoE into your N- and C-terminal fragments been identified?

Keith Crutcher: As far as I know, the question of which proteases are involved hasn't been answered. However, a number of proteases have been shown to be able to cleave apoE into the two major fragments (Wetterau et al. 1988; Aggerbeck et al. 1988). What has impressed me from the outset is the presence of the protease-sensitive hinge domain.

Bruce Teter: The effect of proteolysis on apoE trafficking - isoform dependence, recycling, intracellular fate etc.- all that has not been examined.

Keith Crutcher: Yes, Bruce, this is an interesting point.

Bill Rebeck: I need to leave. Thanks everyone!

Bruce Teter: Bye Bill

Keith Crutcher: See you Bill! Thanks for checking in.

Nico: Thanks, Bill

June: Bye Bill! I'll circulate a transcript, so you can add further comments.

June: So Keith, there's so much going on with ApoE, it's hard to get a sense of what's potentially most important for AD. What are the priority questions for further investigation?

Keith Crutcher: I think it is fair to say that apoE is probably doing something of interest...what exactly remains to be determined. But I think as more studies are done, specific hypotheses can be tested.

June: Do you think the cleavage products are critical?

Keith Crutcher: The evidence we have points to a role for the fragments.

Keith Crutcher: I think we need to know whether E4 toxicity is relevant or just a tissue culture artifact (like amyloid;->)

Bruce Teter: Keith and all - I must run, thanks for organizing this - a good start. Will send specific comments by email.

June: Thanks, Bruce! I'll look for your email.

Keith Crutcher: Thanks Bruce...see you

June: Is the E4 toxicity issue best addressed through transgenic models?

Keith Crutcher: Transgenics might help. Jacob Raber's and Lennart Mucke's mice certainly are suggestive (Raber et al, 1998; Buttini M et al. 2000; also note Raffai & Weissgraber 2002).

June: Which mice, specifically?

Jacob Raber: GFAP- and NSE-apoE mice (Hartman et al. 2001.)

Keith Crutcher: We proposed some time ago to generate mice expressing the truncated form of apoE (one of the many triaged grant proposals). Jacob's mice show evidence of proteolysis.

Marcos Marques: Jacob, has anyone done apoE knockin over an AbPP knockout, do you think that could clarify or separate the role of amyloid and apoE?

Jacob Raber: Not as far as I know. You would need to knock APLP2 out as well.

Keith Crutcher: I need to head out. Sorry for all the trouble folks had with the software today. Thanks for coming. Thank you June and Nico.

Nico: Thanks, Keith, and thanks to all!

Jacob Raber: Best regards.

Steve Rockwood: Sorry to have come in so late--thanks for letting me skulk!

June: Thank you all for participating today. You may send additional questions and comments to me by email. You're also welcome to keep chatting as long as you like.

Keith Crutcher: Yes, I will stay logged on for a while but I may not be able to respond. So don't mind me if I don't reply. Please feel free to send me questions by email.

Background

Background Text
By Keith A. Crutcher

The evidence implicating ApoE in AD has arisen from several lines of research. The immunohistochemical localization of ApoE to senile plaques and tangles (Namba et al., 1991) in the AD brain provided one of the first clues that ApoE may be involved. The most compelling evidence, however, arose from pursuit of a genetic linkage of AD to chromosome 19, which, in turn, led to the establishment of an association between inheritance of the e4 allele for ApoE and the risk of developing AD (Corder et al., 1993). This association has now been replicated in numerous subsequent studies, leading to the general hypothesis that ApoE plays a significant role in the disease (Rebeck et al., 1993; Strittmatter et al., 1993; Bennett et al., 1995; Farrer et al., 1995; Hardy, 1995; Martinoli et al., 1995; Martins et al., 1995; Schellenberg, 1995). But what, exactly, does it do? Several hypotheses have been proposed.

One of the first suggested that ApoE is involved through the binding, transport, and targeting of Aβ or other peptides. Support for this idea came from the observation that the E4 isoform has a much higher affinity for the Aβ peptide than does the E3 isoform (Strittmatter et al., 1993). However, another group soon contradicted this (LaDu et al., 1994), and subsequently reported that the isoform difference in Aβ binding affinity disappears when delipidated preparations of ApoE are used (LaDu et al., 1995).

A related hypothesis holds that altered ApoE-Aβ interactions somehow decrease Aβ clearance from the neuropil (Rebeck et al., 1993).

Evidence has also been presented for antioxidant effects of ApoE: a report that the E4 isoform was less effective in blocking Aβ toxicity than was the E3 isoform (Miyata and Smith, 1996) advanced earlier work that had indicated ApoE may block Aβ toxicity (Whitson et al., 1994). However, another study has reported the opposite, i.e., that E4 potentiates amyloid toxicity (Ma et al., 1996).

The above hypotheses that ApoE may contribute to AD pathology through interactions with Aβ are based on the widespread assumption that Aβ is the primary neurotoxic agent in the disease. This is not the place to take on the amyloid hypothesis. Suffice it to say that some of us remain unconvinced that the role of amyloid is either primary or sufficient to account for the neuropathology and symptoms of AD. Thus, consideration of alternative hypotheses appears warranted.

ApoE could be involved through a mechanism unrelated to its interaction with Aβ. For example, results presented by Strittmatter and colleagues indicated that the E3 isoform has a higher affinity for the microtubule component tau than does the E4 isoform. Since tangles are composed of hyperphosphorylated tau, the authors proposed that the E3 isoform normally serves to bind tau, thus preventing its abnormal phosphorylation (Strittmatter et al., 1994).

According to this idea, an inherited E4 isoform will render its carrier more susceptible to tau phosphorylation, thereby leading to its accumulation in the form of tangles and subsequent disruption of neuronal function. Other effects of ApoE have led to related hypotheses.

For example, isoform-specific effects of ApoE on neurite outgrowth have prompted the suggestion that individuals carrying the e4 allele have reduced compensatory responses to injury. The E4 isoform inhibits neurite outgrowth (Poirier, 1994; Teter et al., 1999). ApoE is also capable of binding to, and potentiating the survival effects of, ciliary neurotrophic factor (CNTF) (Gutman et al., 1997). The absence of isoform differences in this activity, however, leave unclear how this relates to ApoE's role in AD.

Moreover, ApoE has been implicated in oxidative stress (Ramassamy et al., 2000) and/or oxidative defense (Pedersen et al., 2000).

Absence of E3 or Presence of E4?

The preceding hypotheses all are partially supported by existing data, but the evidence is indirect. Strikingly, each of these proposed mechanisms assumes a positive role for ApoE function, such that the isoform-associated risk of disease would reflect the relative failure of the E4 isoform of performing this function. However, several recent lines of evidence suggest that the presence of E4-not the absence of E3-may be most relevant to understanding the contribution of ApoE to disease risk and pathology.

For example, evidence is accumulating for the idea that ApoE4 may have a great stimulatory effect on intracellular pathways. Several observations support the possibility that ApoE may have signaling effects in neurons, including the demonstration of elevated intracellular calcium following exposure to full-length or truncated ApoE (Muller et al., 1998; Tolar et al., 1999; Ohkubo et al., 2000). Most intriguingly, ApoE4, and a peptide derived from its receptor binding domain, have recently been reported to activate CREB (Ohkubo et al., 2000), but ApoE3 does not do that.

These observations are consistent with the possibility of isoform-specific differences in ApoE's ability to affect intracellular signaling through receptors of the LDL family. That these receptors may play such a role is now supported by several studies.

ApoE may affect neurons in more ways than its presumed role of mediating cholesterol transport. This idea gains support from studies indicating that ApoE exhibits isoform-specific neurotoxicity, demonstrated for several in vitro systems including chick sympathetic and cortical neurons, rat hippocampal neurons, F11 neuronal cells, and neuroblastoma cells (Marques et al., 1997; Jordan et al., 1998; Hashimoto et al., 2000; Cedazo-Minguez et al., 2001). Importantly, however, ApoE3 can also exhibit neurotoxic effects, albeit at higher concentrations.

Several studies have found that truncated ApoE and peptides derived from the N-terminal receptor-binding domain are neurotoxic, raising the possibility that ApoE's neurotoxic effects are due, at least in part, to these regions of ApoE (Crutcher et al., 1994; Marques et al., 1996; Tolar et al., 1997; Moulder et al., 1999; Hagiwara et al., 2000). Treatment of cells with ApoE peptide resulted in a rapid influx of calcium that could be significantly blocked by RAP and MK-801, ligands for LRP and NMDA-type glutamate receptors, respectively ( Tolar et al., 1999). However, other groups have not found consistent evidence for a role of LRP in mediating the toxicity of ApoE or ApoE peptides [Moulder et al., 1999; Hagiwara et al., 2000].

Additional evidence supports the view that the presence of E4 is more important than the absence of E3. It includes the finding that ApoE4 inhibits neurite outgrowth and can override the neurite-stimulatory effect of ApoE3 (reviewed in Teter, 2000), as well as emerging evidence that transgenic expression of ApoE4 can have negative behavioral effects that can dominate over the effect of ApoE3 (Raber et al., 1998; Buttini et al., 2000; Raber et al., 2000; Hartman et al., 2001).

Finally, emerging evidence suggests that promoter polymorphisms in the ApoE gene, which are associated with increased expression, are also tied to increased risk of the disease, regardless of isoform (reviewed by Bullido and Valdivieso, 2000.) These data are hard to reconcile with the view that ApoE3 is playing a positive role and that its absence leads to greater risk.

Novel hypothesis

We have proposed that ApoE plays a direct role in AD pathology through its proteolysis, leading to the generation of truncated neurotoxic and amyloidogenic fragments.

We suggest that proteolysis of ApoE in the brain generates two major fragments, 22 kDa N-terminal and 10 kDa C-terminal ApoE, which have different fates.

The N-terminal fragment is postulated to play a role in the neurotoxicity reviewed above (Marques et al., 1996; Crutcher et al., 1997; Tolar et al., 1997; Tolar et al., 1999), possibly involving GTPase (Hashimoto et al., 2000) and/or CREB activation (Ohkubo et al., 2000). These effects may be mediated through cell surface receptors, such as LRP, or through related pathways. The findings that full-length ApoE toxicity is mediated by the generation of truncated ApoE (Marques et al., 1997), and that cytosolic expression of ApoE elicits neurotoxicity (DeMattos et al., 1999) also suggest that ApoE proteolysis is important to neurotoxicity.

Truncated ApoE may also contribute to neurofibrillary pathology. ApoE exhibits isoform-specific effects in promoting microtubule polymerization (Bellosta et al., 1995) and tau phosphorylation in vitro ( Strittmatter et al., 1994; Strittmatter et al., 1994). Human ApoE transgenic mice develop tau hyperphosphorylation (Tesseur et al., 2000) and axonal degeneration ( Tesseur et al., 2000). In addition, synaptic loss (Cambon et al., 2000) and CNS neurodegeneration have been reported in human-ApoE4 transgenic mice, and a possible role for "neurotoxic ApoE4 derivatives" was noted (Buttini et al., 2000). It is noteworthy that the ApoE3/4 mice in this study showed the presence of truncated ApoE, analogous to the N-terminal truncated ApoE in human brain (Marques et al., 1996; Cho et al., 2001; Zhang et al., 2001). And of special interest is the recent demonstration that in-vitro expression of C-terminally truncated ApoE4 causes the formation of tangle-like structures in transfected cells ( Huang et al., 2001).

The C-terminal fragment, on the other hand, is proposed to bind and deposit with amyloid, leading to plaque formation. This is consistent with the presence of C-terminal ApoE in amyloid-immunoreactive plaques (Aizawa et al., 1997) and the recovery of C-terminal ApoE from plaques (Naslund et al., 1995; Wisniewski et al., 1995). Results from transgenic mouse lines are also informative. The highly reproducible formation of plaques observed in AbetaPP transgenic mice is largely prevented when this protein is overexpressed in mice lacking ApoE (Holtzman et al., 1999). Furthermore, ApoE appears to be required for the appearance of neuritic pathology in these mice (Bales et al., 1999; Holtzman et al., 2000). Although there is no proof that the C-terminal portion of ApoE is responsible for this effect, abundant evidence shows that the C-terminal domain of ApoE exhibits high affinity for amyloid (Strittmatter et al., 1993; Wisniewski et al., 1993; Naslund et al., 1995; Aizawa et al., 1997; Lins et al., 1999; Pillot et al., 1999).

Immunohistochemistry provides yet more evidence for the ApoE proteolysis hypothesis. Plaques and neurofibrillary tangles show differential staining with anti-ApoE antibodies. Antibodies against N-terminal ApoE epitopes stain tangles more intensely than plaques. In contrast, a C-terminal epitope antibody stains plaques but few neurofibrillary structures (Zhang et al., 2001). Together with the demonstration of an increased truncated ApoE/full-length ApoE ratio (Zhang et al., 2001), these findings support the hypothesis that ApoE proteolysis is relevant to Alzheimer's disease.

ApoE proteolysis

Some evidence suggests that ApoE peptide fragments are generated in other systems. For example, a study investigating the role of ApoE in peripheral nerve injury demonstrated the presence of immunoprecipitated low-molecular weight fragments most likely derived from ApoE (Ignatius et al., 1986). Rabbit Muller cells (Amaratunga et al., 1996) and murine microglia cells (Xu et al., 2000) also produce truncated ApoE in vitro.

Our investigations provide direct evidence that the brain and CSF normally contain ApoE fragments, the most abundant of which is the 22 kDa N-terminal truncated species (Marques et al., 1996). To clarify whether truncated ApoE was generated as an artifact of postmortem delay, fresh human and transgenic ApoE mice tissues were used; both contained truncated ApoE (Zhang et al., 2001). Other groups have recently described the presence of truncated ApoE in human brain (Cho et al., 2001; Huang et al., 2001) and in ApoE-transgenic mice (Buttini et al., 2000; Zhang et al., 2001).

Historically, ApoE metabolism has been investigated in light of its participation in lipid transport and lipid metabolism (Weisgraber, 1994; Dominguez et al., 1999; Mahley and Ji, 1999; Ho et al., 2000). Lipids have not only been implicated in ApoE internalization (Innerarity et al., 1979; Weisgraber, 1994) and in modulation of its conformation (Lund-Katz et al., 2000; Segelke et al., 2000) but also in its secretion and degradation (Ye et al., 1992; Duan et al., 1997). Most studies used macrophages or hepatic cell lines to investigate the type and intracellular location of the protease(s) involved in ApoE degradation (Ye et al., 1992; Ye et al., 1993; Deng et al., 1995). Although it is likely that the protease(s) that cleave ApoE are cell-type dependent, in vitro experiments have also shown that a wide range of proteases can cut ApoE, yielding N- and C-terminal fragments (Wetterau et al., 1988).

Toward a Resolution - Critical Experiments

According to this hypothesis, then, the higher risk associated with the ApoE4 allele arises from the greater toxicity of this isoform and/or isoform-specific susceptibility to proteolysis. The role of amyloid is suggested to be due to its effect on the binding, accumulation, synthesis, or proteolysis of ApoE.

This hypothesis is consistent with epidemiological data demonstrating a greater risk of Alzheimer's with an inherited E4 allele. It does not, however, posit that only the E4 isoform is involved in the disease. In fact, the hypothesis assumes that the isoforms have the same function but that the relatively greater toxicity associated with the E4 isoform and/or its greater susceptibility to proteolysis confers increased risk. The primary sequence of the receptor-binding domain, which is associated with the toxic activity, is almost identical in all three of the common ApoE isoforms. Therefore, the difference in toxicity is presumably due to structural alterations arising from the single amino acid differences that alter the three-dimensional conformation of the isoforms.

Several predictions follow from this hypothesis, which should be tested:

1. ApoE plays a direct role in Alzheimer's neuropathology and is not simply a supporting actor. If this were true, one would expect that a lack of ApoE should prevent AD. Although rare examples of human ApoE "knock-outs" are known, there is insufficient data to say whether the risk for Alzheimer's is altered in these individuals. Intriguingly, however, ApoE2 can in some ways be considered the most inactive form of ApoE (for example in terms of receptor binding), yet it confers apparent protection against disease.

2. ApoE proteolysis is critical for amyloid deposition. This possible prediction follows from the argument that the C-terminal domain of ApoE binds to amyloid and is most abundant in plaques. The demonstration that amyloid deposition is dramatically reduced in transgenic AbetaPP mice that have no ApoE is the only direct evidence that ApoE is involved in amyloid deposition. It would be worth testing whether the C-terminal fragment of ApoE is recoverable from the amyloid deposits in AbetaPP mice. An alternative interpretation is that the binding of full-length ApoE to amyloid precedes ApoE proteolysis and the generation of neurotoxic fragments. Either way, fragments should be recovered.

3. Neurofibrillary tangle formation involves interaction with truncated ApoE. It appears that the ApoE staining associated with tangles is due to a truncated form of ApoE. Yet it is unclear how this fragment came into association with the tangles, i.e. whether this is secondary to receptor activation or follows endocytosis of ApoE fragments. Nor is it clear whether the presence of tangles correlates with the putative neurotoxic effects of truncated ApoE. It is possible that tangle formation actually represents a protective mechanism against the neurotoxicity of ApoE fragments.

4. Expression of the truncated form of ApoE should lead to neurotoxicity in vivo. This is perhaps the most important prediction and could be investigated with transgenic models. Although some of the known transgenic mice do show evidence of ApoE fragments, it is unclear whether the presence of full-length ApoE would interfere with the activity of these fragments. Thus, a transgenic model expressing specific ApoE fragments could be useful in testing the predictions of this hypothesis. Transgenic expression of ApoE4 has recently been reported to result in relatively selective memory deficits in the absence of overt AD-like pathology; this supports a direct role for ApoE4 in cognitive deficits ( Hartman et al., 2001).

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The Role of ApoE in Alzheimer's Disease: An Alternative View

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