The Role of ApoE in Alzheimer's Disease: An Alternative View
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.
View Transcript of Live Discussion — Posted 30 December 2001
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).
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.
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.
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).
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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