Being both an active scientist and a part-time reporter leads to some interesting situations. Most of the time, my scientific background could be considered an advantage when evaluating reports because I should have a better understanding of the field as compared to those not working in it. On the other hand, my scientific views necessarily lead to a bias in both the work that I do and the news that I report. The most direct conflict arises when evaluating the work done in my own laboratory. Obviously, I think the work is important and relevant, otherwise I wouldn’t be doing it. Whether it is "newsworthy" is harder to assess. So before taking advantage of my position as a reporter to highlight work from my lab, I waited to see what kind of response there was to a poster (abstract 576.7) we presented at this meeting. There was a continuous stream of interested individuals (folks who actually stopped to read the poster and ask questions), most of whom expressed the opinion that they thought the work was both interesting and potentially important. So with that as my polling sample, I am providing a brief summary of the salient results.
As noted in my report on the Huang talk (abstract 202.8), ApoE’s role in AD has been difficult to pin down. We had reported some years ago that ApoE peptides, the N-terminal fragment of ApoE (truncated ApoE) and full-length ApoE exhibit neurotoxic effects with the E4 isoform being more toxic. There has also been a fair amount of evidence that ApoE contributes to amyloid deposition, perhaps mediated by binding to amyloid through the C-terminal portion of ApoE. Whether ApoE fragments exist in the human brain has been a controversial claim (I can say this with some authority). The results presented in our poster suggest that truncated ApoE is present in human brain and that there is an increase in the proportion of this fragment in AD brain as compared to control tissue (the highest ratio being found in ApoE4/4 cases). Furthermore, immunohistochemistry carried out with different ApoE antibodies suggests that apoE staining of plaques is obtained with almost any anti-ApoE antibody, but is especially prominent with a monoclonal antibody raised against a C-terminal epitope. The same antibody, however, gives little staining of the neurofibrillary pathology. Antibodies directed against the N-terminal part of ApoE, on the other hand, reveal the neurofibrillary pathology.
The bottom line hypothesis is that ApoE contributes to both plaque and tangle formation via C-terminal and N-terminal fragments, respectively, that are products of ApoE proteolysis. The pathway to plaque formation presumably involves amyloid deposition through interactions with the C-terminal fragment. How tangles might form is still a matter of speculation, but there is increasing evidence that the receptor-binding domain of ApoE is involved in signaling and, perhaps, neurotoxic effects. Once ApoE gets internalized, it may be able to interact with cytoskeletal components to affect tangle formation as suggested by the work of Huang et al. (reported elsewhere). So there it is. A working hypothesis that may have some heuristic value for understanding the role of ApoE in AD. Or maybe not. The fun of science is growing hypotheses and seeing whether they thrive. The lifespan of this particular idea remains to be determined.—Keith Crutcher
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