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  1. This study from Dale Bredesen’s group identifies TAZ and YAP as two potential downstream agents of APP-modulated gene transcription in a luciferase-reporter system. Since the γ-secretase inhibitor DAPT blocks the reporter activity, the authors suggest that it is mediated via the APP Intracellular domain (AICD), which, upon release from the membrane, enters the nucleus and activates the reporter gene in a tripartite complex with Mint3 and TAZ/YAP. This paper adds Mint3 to the list of proteins (Fe65 and JIP-1B) that are known to bind APP/AICD and to activate gene transcription.

    As Bredesen admits, the relevance of APP/AICD interaction with TAZ/YAP to AD pathology remains to be established. Nonetheless, it is clear that these studies add further support to the view that APP cytoplasmic domain (ACD) and the free, cleaved AICD are important players in APP biology. ACD/AICD is known to interact with about a dozen or so proteins, which provide the molecular basis for the functional importance of ACD/AICD and the diverse array of biological effects it exerts. The challenge faced by the field, and succinctly stated by Suzanne Guennette above, is how to ensure that these interactions occur at the physiological protein level and are not induced by protein overexpression. Such experiments are technically not easy, and for a field so focused on “Aβ-ology,” perhaps not compelling. Yet, it is difficult to see how we can get a complete picture of APP pathophysiology, and hence of AD pathogenesis, without such lines of investigation.

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