One of the earliest clues that apoE may contribute to AD pathology was the immunohistochemical demonstration by Namba and colleagues that ApoE was present in both plaques and tangles. ApoE did not really get serious consideration as a vital player, however, until the genetic association with ApoE4 was established by Roses and co-workers. Even so, the role of ApoE has been largely viewed as subordinate to that of amyloid, serving, at best, as a chaperone for the Aß peptide. Along the way there have been hints that ApoE may be more directly involved. For example, under some tissue culture conditions ApoE4 (and fragments of this protein) is toxic to neurons. [Disclaimer: This reporter contributed to the initial studies demonstrating ApoE toxicity and remains a firm believer in its relevance to AD pathology, i.e., I am biased. See the report on abstract 576.7 for more biased reporting.]
At the World Alzheimer Congress this past July, a group from the Gladstone Institute reported that C-terminal-truncated forms of ApoE (truncation that results in cytosolic accumulation of the protein) give rise to tangle-like structures when expressed in Neuro-2a cells. This week, the same investigators provided an update on this work (poster 202.8). In addition to documenting the filamentous nature of the tangle-like structures using electron microscopy, they found that the tangles were immunopositive for phosphorylated tau (p-tau) and the heavy neurofilament protein. Furthermore, ApoE co-precipitates with p-tau from the transfected cells. Intriguingly, treatment of the cells with Aß leads to greater proteolysis of ApoE. They further demonstrated that truncated ApoE fragments are present in human brain homogenates (in agreement with our own earlier studies) with the important additional finding that there are differences in the types of fragments present in the insoluble pellet and the supernatant. In particular, the ApoE fragments are in much greater abundance in the pellet from AD homogenates as compared to control homogenates, suggesting their precipitation with other components. They also demonstrated higher molecular weight complexes (approx. 220 kDa) that form from ApoE and p-tau. In answer to a question from the audience, Dr. Huang noted that these transfections inevitably lead to cell death within two to three days, suggesting that these constructs are ultimately toxic.
What does it all mean? Well, for one thing, the finding that intracellular truncated ApoE may contribute to cytoskeletal abnormalities resembling tangles emphasizes the importance of the original observation of Namba et al. that AD tangles stain for ApoE. In addition, if the effects of truncated ApoE are connected in some way to the previously reported toxic effects of ApoE, this could provide a hint as to the role of this protein in AD neuropathology, in addition to its putative role in contributing to amyloid deposition. (More on this idea is found in the report on abstract 576.7.)—Keith Crutcher. Abstract #202.8.
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