. Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?. J Biol Chem. 2021 Jan-Jun;296:100489. Epub 2021 Mar 1 PubMed.


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  1. Checler et al. have published a very informative review of the evidence that the precursor to Aβ, the “βCTF” or “C99” fragment of APP, is likely a very important (if not the most important) derivative of APP acting in the pathogenic process leading to Alzheimer’s disease. The authors have done a wonderful job of collecting a great many various lines of evidence into their paper. There are a few points I would like to make in association with this:

    1) The authors rightly point out that much of the genetic evidence from fAD mutations identified in APP is consistent with a pathogenic role for increased C99 formation. I think that this provides a more parsimonious explanation for the pathogenic effect of these mutations than qualitative changes in the form of Aβ.

    2) The idea that C99 is a (or the) pathogenic agent resulting from fAD mutations in APP is not actually inconsistent with the Amyloid Cascade Hypothesis as originally described. In their 1992 paper declaring the hypothesis (Hardy et al., 1992), Hardy and Higgins wrote, “Our cascade hypothesis states that AβP itself, or APP cleavage products containing AβP, are neurotoxic and lead to neurofibrillary tangle formation and cell death.”

    3) The authors describe two main hypotheses regarding the effects of fAD mutations in the presenilin genes: gain-of-function and loss-of-function of γ-secretase. Of course, loss-of-function is consistent with accumulation of C99 and the authors rightly point to the study of 138 fAD mutations of PSEN1 by Sun et al. (Sun et al., 2017) as demonstrating that 90 percent of the mutations do show reduced γ-secretase activity (cleavage of C99) in in vitro studies. However, they are incorrect in reporting that the Sun et al. paper showed these mutations as acting in a dominant negative manner. It was Heilig et al. (Heilig et al., 2013) with Shen and Kelleher who first demonstrated the dominant negative effect, but they only examined mutations causing reduced γ-secretase activity. Although Kelleher and Shen (Kelleher and Shen, 2017) claimed, regarding Sun et al.’s work, that “their results point to loss of γ-secretase activity as the primary molecular defect imposed by pathogenic PSEN1 mutations” this ignores the fact that ~10 percent of the mutations analysed by Sun et al. (at least 11 mutations) caused increased γ-secretase cleavage of C99. Independent confirmation of increased γ-secretase activity for one of these mutations has been provided by Zhou et al. (Zhou et al., 2017) (for PSEN1 S365A). Any unified explanation for the action of fAD mutations in the presenilin genes cannot ignore these numerous mutations that appear to increase γ-secretase activity. The one universally consistent phenomenon for the presenilin mutations causing fAD is that these always cause production of at least one transcript isoform preserving the original open reading frame (i.e., allowing translation of a “full-length” protein). We have previously described this as the “reading frame preservation rule.” As we noted previously (Jayne et al., 2016), a case can be made that the fAD-causative effect of presenilin mutations is expressed through their effect on the function of the presenilin holoprotein, an idea that is consistent with the reading frame preservation rule and the observations of the Nixon laboratory (Lee et al., 2010) that fAD mutations disrupt lysosomal acidification by a γ-secretase-independent effect on holoprotein function. One possibility (among others requiring testing) for a unified effect of presenilin fAD mutations is that their deleterious effects on endolysosomal acidification in vivo may reduce γ-secretase activity to the extent that this overwhelms any increased intrinsic γ-secretase activity of a mutant enzyme complex (since normal endolysosomal acidification appears important for γ-secretase cleavage of Notch (Valapala et al., 2013; Yan et al., 2009) and so might similarly affect C99).

    4) Lastly, the accumulation of Aβ in brains has been viewed as “toxic” since, for many years, Aβ was not thought to fulfill any pro-survival purpose. This also made Aβ an acceptable target for drugs blocking its supposedly toxic action. However, it would be unfortunate if C99 was also perceived this way (by being thought of as “toxic”). The work of Pera et al. (Pera et al., 2017), Jiang et al. (Jiang et al., 2019), Montesinos et al. (Montesinos et al., 2020) and others clearly demonstrates that C99 has important roles in cell physiology and that it would likely be unwise to inhibit completely its action in cells rather than modulating it.


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