. APP processing and synaptic plasticity in presenilin-1 conditional knockout mice. Neuron. 2001 Sep 13;31(5):713-26. PubMed.

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  1. Keeping in mind everything that is currently known about PS1 and its main substrate, APP, this paper by Yu et al. was a pioneer in studying the consequences of PS1 inactivation on cognitive deficit. Despite not being recent, there are still some ideas that can be drawn from reading it.

    In the cortex of the PS1 cKO mouse, two carboxy-terminal fragments, C89 and C83, were clearly increased as a result of increased availability of substrate, APP, for the cleavage reactions of α- and β-secretase, respectively. Both were elevated by as much as 30-fold (Figure 4 of the paper), whereas C99, another β-secretase cleavage product, was only increased threefold.

    Apart from the increased availability of APP for β cleavage, less than half of the total amount of Aβ (Aβ40 and Aβ42) forms in the cortex of PS1 cKO mouse cortex compared to control (Table 2 of paper), because less than half of the amount of C99 is cleaved by γ-secretase. In other words, something has happened with γ cleavage, because PS1 was conditionally knocked out. But in addition, the relatively small increase in C99 is curious, since overexpression of BACE leads to robust increases in C99 over C89 (see Lee et al., 2005). Why the small increase in C99 in PS1 knockouts? It seems that in this case, BACE C99 cleavage is linked to PS1, suggesting that APP might have to be physically attached to the γ-secretase complex before C99 β cleavage occurs.

    References:

    . BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo. J Cell Biol. 2005 Jan 17;168(2):291-302. PubMed.