One of the great unsolved mysteries of Alzheimer's disease is the link between the disease's two major lesions: Aβ amyloid plaques and tau tangles. Proponents of the amyloid cascade hypothesis presume that the former causes the latter. A fascinating alternative scenario is emerging from the laboratory of Peter Davies and his colleagues, which suggests that pathogenic changes to APP and tau may instead both be triggered by a single underlying event (Abstract 956). The Davies lab reported that phosphorylation of threonine 231 on tau results in a conformation that is strikingly similar to phosphorylation of threonine 668 on APP. Not only do many monoclonal antibodies raised against either of these two phosphoepitopes cross-react with both (and with no other phosphoepitopes), but both phosphorylated sites provide a substrate for Pin1, a molecule involved in regulation of mitosis. What's more, staining of Alzheimer's brain tissues with monoclonal antibodies shows that phosphothr 668 APP occurs in hippocampal and cortical neurons-and only in neurons that also stain for phosphothr 231 tau. The phosphothr 668 APP staining could clearly be seen in the lysosomal compartment.
What do these findings suggest? On the downstream side, Davies and colleagues previously have shown that Pin1 is present in Alzheimer's tangles, and that its binding to phosphothr 231 tau alters the conformation of tau, disrupting its ability to promote microtubule formation and possibly promoting PHF formation. Davies speculates that Pin1 binding to APP might result in increased Aβ formation. On the upstream side, Davies reported that cdc2 phosphorylates threonine 668 on APP, and suggested that a cdc2-like enzyme is involved in phosphroylation threonin 231 on tau. Others propose cdk-5 as a likely candidate. Much remains to be worked out, but one implication was clear: If Aβ accumulation and tau pathology are the result of parallel pathways initiated by a common trigger, then drugs targeting Aβ are not likely to halt tau pathology.—June Kinoshita
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