. Effect of potent γ-secretase modulator in human neurons derived from multiple presenilin 1-induced pluripotent stem cell mutant carriers. JAMA Neurol. 2014 Dec;71(12):1481-9. PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This paper brings up an important topic, namely the uncertainty of current approaches in the preclinical evaluation of novel drug candidates for Alzheimer’s disease. As stated by the authors, many studies have been performed on transfected cell lines and transgenic animal models that have a marked overexpression of the protein of interest, which may not correspond to how drug candidates act in human neuronal cells, or more so in the human brain.

    In the present study, the effect of γ-secretase modulators (GSMs) and γ-secretase inhibitors (GSIs) on Aβ metabolism was tested on human induced pluripotent stem cells (iPSCs). Following application of a GSM, a biomarker pattern characterized by a reduction in Aβ42, Aβ40, and Aβ38 without any change in total Aβ was found. To get this equation balanced, an increase in other Aβ species is to be expected, and using western blot instead of ELISA, an increase of smaller peptides including Aβ39 and Aβ37 was found.

    The results, which differ from those obtained by other cellular models and transgenic animals, may, as the authors suggest, be due to the huge overexpression of APP in these models. This suggestion is also supported by data from a previous study in which a GMS was tested in healthy beagle dogs. In ventricular CSF samples, a modest reduction in Aβ42 and Aβ40 was accompanied by a marked increase in Aβ37 (Portelius et al., 2010).

    The final question will be: Which model will most accurately reflect the biomarker signature, i.e., the effect on Aβ metabolism by drug candidates, in the human brain? Further translational studies, comparing experiments performed in different models (either cellular or animal) with results from human studies, will be necessary to answer this question. Encouraging data suggesting that small and short-term Phase 1 studies in healthy volunteers will provide solid proof of target engagement was recently reported in a study of a BACE1 inhibitor. A dose-dependent decrease in both plasma Aβ, CSF Aβ, and sAPPβ was found, corresponding to the change found in plasma and CSF in beagle dogs, and in brain tissue in APP transgenic mice (May et al., 2011). 

    References:

    . Acute effect on the Aβ isoform pattern in CSF in response to γ-secretase modulator and inhibitor treatment in dogs. J Alzheimers Dis. 2010;21(3):1005-12. PubMed.

    . Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J Neurosci. 2011 Nov 16;31(46):16507-16. PubMed.

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. Forget Mice—Are Human Cells Better for Drug Testing?

Mutations

  1. PSEN1 M146L (A>C)
  2. PSEN1 M146L (A>T)