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Hutter-Paier B, Huttunen HJ, Puglielli L, Eckman CB, Kim DY, Hofmeister A, Moir RD, Domnitz SB, Frosch MP, Windisch M, Kovacs DM. The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron. 2004 Oct 14;44(2):227-38. PubMed.
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University of the Saarland
Dora Kovacs's paper on ACAT inhibition in transgenic mice is certainly a milestone on the way to understanding the role of lipids in AD. The very pronounced effect ACAT inhibition has on Aβ deposition is fascinating and should prompt more efforts into this direction. Especially so, because their data suggest that ACAT inhibition triggers a novel non-secretase-related pathway that circumvents Aβ generation. This is important, because it shows that it might be combined with other approaches that target secretases and/or Aβ removal, thus multiplying total effect strength. For the time being, it appears that ACAT inhibition could find its place preferentially in prevention of AD, which is in accordance with the use of young animals that just started to build amyloid deposits. The true mechanism by which ACAT inhibition results in lowered brain Aβ levels remains somewhat enigmatic. Deciphering this mechanism will be important to design safe and effective treatment approaches; I count on it that Dora will find an answer to this pretty soon, too.
Nevertheless, at the end of the day, clinical usefulness will anyway depend much more on the magnitude of unwanted side effects ACAT inhibition has than on whether it removes a bit more or less Aβ. The ongoing avasimibe trial raises some hopes that this question could soon be addressed in an avasimibe AD-treatment prospective clinical trial.
But there is also a second aspect that fascinates me. This is the presence of a cholesteryl-ester responsive cleavage site in the APP luminal domain. This was not stressed in this publication, but it clearly indicates the ACAT inhibition effect isn't there just by chance, rather than that APP processing must have evolved to respond to cholesterol-ester concentration. Clearly a sign that cholesteryl-esters are to be watched in AD.
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