The findings in the paper by Zhao and colleagues are intriguing: The presence of a 46-residue form of Aβ inside the cell, but not secreted, raises the question of whether this longer, presumably more amyloidogenic Aβ might serve as a nidus for intracellular amyloid deposits. Nevertheless, the claim for a new cleavage site is overstated. It is well-known that cleavage at the γ site is heterogeneous, giving 38-43 residue variants of Aβ, so it is not too surprising that the presenilin-containing γ-secretase complex can also produce small amounts of Aβ46. Indeed, we found that purified γ-secretase can produce small amounts of Aβ45 (Fraering et al., 2004).

Certain non-transition-state analogue inhibitors are shown to dramatically increase intracellular Aβ46 in a presenilin-dependent manner while decreasing secreted Aβ40 and 42. Apparently, these compounds, while primarily inhibiting γ-secretase, also induce a conformational change in the protease complex, which still retains some residual activity. What little activity remains has...  Read more

The findings in the paper by Zhao and colleagues are intriguing: The presence of a 46-residue form of Aβ inside the cell, but not secreted, raises the question of whether this longer, presumably more amyloidogenic Aβ might serve as a nidus for intracellular amyloid deposits. Nevertheless, the claim for a new cleavage site is overstated. It is well-known that cleavage at the γ site is heterogeneous, giving 38-43 residue variants of Aβ, so it is not too surprising that the presenilin-containing γ-secretase complex can also produce small amounts of Aβ46. Indeed, we found that purified γ-secretase can produce small amounts of Aβ45 (Fraering et al., 2004).

Certain non-transition-state analogue inhibitors are shown to dramatically increase intracellular Aβ46 in a presenilin-dependent manner while decreasing secreted Aβ40 and 42. Apparently, these compounds, while primarily inhibiting γ-secretase, also induce a conformational change in the protease complex, which still retains some residual activity. What little activity remains has altered substrate specificity, producing only Aβ46.

Aβ46 is apparently the major intracellular form of Aβ, but this does not mean, as the authors claim, that this is another major cleavage site in APP. Under normal conditions (in the absence of non-transition-state analogue inhibitors), it is clearly a very minor cleavage site, and Aβ46 is simply not efficiently secreted from the cell, probably due to the fact that it contains a good portion of the APP transmembrane domain.

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