. CNS amyloid-β, soluble APP-α and -β kinetics during BACE inhibition. J Neurosci. 2014 Jun 11;34(24):8336-46. PubMed.

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  1. A very interesting finding, indeed!

    View all comments by Saak Ovsepian
  2. The primary expected therapeutic mechanism of action of BACE inhibition is to lower toxic Aβ burden in the CNS via inhibition of its synthesis from APP. This is founded on the strongest human genetic evidence possible, including identification of both risk-enhancing and protective mutations. The relative therapeutic impact of increased CNS sAPPα in response to CNS BACE inhibition is unknown. Several physiological roles of sAPPα have been proposed (e.g. a neuroprotective role), but none are yet widely accepted and understanding of the biology of sAPPα is still evolving. It is important to note that sAPPα levels were not decreased by the BACE inhibitor.

    The reasons for the differing magnitude of the effect of BACE inhibition on sAPPα levels detected by either ELISA or LC-MS are not understood.  However, the modest increase in ELISA sAPPα, a measure of total sAPPα, demonstrates that this pathway contributes to alternate APP clearance when BACE is considerably inhibited.  As noted in the manuscript, we continue to advance a comprehensive model of CNS APP processing in the non-human primate, including data from both ELISA and SILK/LC-MS during steady state conditions and also following both BACE and gamma-secretase inhibition.  This more comprehensive model is likely to contribute to further understanding of APP processing kinetics.

    View all comments by Mary Savage
  3. Inhibition of α-secretase does not affect BACE1 processing in neuroblastoma cells expressing endogenous APP (Gandhi et al., 2004). Thus, the two pathways don't appear to compensate for each other, but appear to occur in independent compartments.

    View all comments by Kumar Sambamurti

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