. The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein. FASEB J. 2006 Mar;20(3):512-4. PubMed.

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  1. Activation of α-secretase activity to increase non-amyloidogenic processing of APP is definitely one of the hottest topics among the current experimental approaches in AD. Undoubtedly, it also constitutes a major challenge (but are there minor ones in AD?), because inhibition, not activation, is the natural pharmacological reflex.

    This paper offers another handle on the problem, via the PACAP peptide and its PAC1, G-protein coupled receptor that activates ADAM10. This complements the previous identification of ADAM10 as the major α-secretase activity acting on APP in vivo (Postina et al., 2004). The activation of ADAM10 by the PACAP-PAC1 signaling cascade, although not yet understood in molecular terms, appears now ready to be tested in vivo in a transgenic model. Thereby several other problems can be faced, given that PACAP is a peptide and therefore not the best-suited in vivo ligand, and in terms of triggering pharma's interest. Proof-of-principle in vivo is nevertheless needed to upgrade the PACAP-PAC1 switch to the status of "most exciting" therapeutic target.

    References:

    . A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest. 2004 May;113(10):1456-64. PubMed.

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