Inhibiting ACAT, a cholesterol-modifying enzyme, may prove a viable therapy for preventing or slowing the progression of Alzheimer disease, according to a report in the October 14 Neuron. A multi-institution collaboration led by Dora Kovacs at Massachusetts General Hospital, Boston, shows that inhibiting the enzyme limits production of amyloid-β (Aβ), reduces plaque load, and prevents learning and memory losses in a mouse model of the disease.

ACAT (Acyl coenzyme A: cholesterol transferase) catalyzes the esterification of cholesterol, redistributing the lipid from the plasma membrane into cytoplasmic droplets. Kovacs and colleagues have previously reported that blocking the enzyme attenuates production of Aβ in primary neurons (see ARF related news story). Now, joint first authors Birgit Hutter-Paier at JSW-Research Forschungslabor GmbH, Graz, Austria, and Henri Huttunen at MGH, along with other researchers from these institutions and the Mayo Clinic, Jacksonville, Florida, extend those observations to transgenic animals. They tested CP 113,818, an ACAT inhibitor developed by Pfizer, in mice expressing human amyloid precursor protein harboring two different kinds of mutation—the London mutation, which results in an isoleucine instead of a valine at amino acid number 717, and the Swedish double mutation, methionine and leucine for lysine and asparagine at positions 670 and 671, respectively. These animals develop amyloid plaques in the brain, and by six months old show signs of cognitive decline.

Because CP 113,818 is so poorly absorbed, the authors administered it in slow-release capsules, surgically implanting a two-month supply into four and a half-month-old mice. When the authors checked brain pathology at six and a half months, they found a considerable reduction in plaque load, as judged by both thioflavin S and antibody (6E10 antibody) staining. Treated animals had only about 26 plaques per square micrometer of cortex, while placebo-treated animals had over 200. The benefit was greatest in the hippocampuses of female animals, where the plaque load was only one percent of that found in sham-treated animals. In addition, when the authors measured soluble Aβ by ELISA, they found that levels of soluble Aβ1-42 were reduced by over 30 percent, a result that was statistically significant.

These particular transgenic mice only begin to show a hint of cognitive decline at six months. Nevertheless, the authors found that those given the ACAT inhibitor preformed consistently better in the Morris water maze—particularly the female animals. In these mice, improvement was statistically significant, which suggests that males, where the AD-like symptoms develop more slowly, may also benefit as they age. “We are presently examining the effect of the inhibitor on older animals,” Kovacs revealed.

These findings may put ACAT inhibitors on the fast track for development for AD. Already Pfizer has Avasimibe® in phase III clinical trials for the treatment of atherosclerosis, and it is already “considered safe for human use with a good therapeutic window,” write the authors.—Tom Fagan.

Reference:
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 October 14;44:1-20. Abstract

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  1. 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.

References

News Citations

  1. Cellular Compartments Provide New Wrinkle—and a New Target?—in Cholesterol

Paper Citations

  1. . 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.

Further Reading

Papers

  1. . 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.

Primary Papers

  1. . 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.