. Deletion of presenilin 1 hydrophilic loop sequence leads to impaired gamma-secretase activity and exacerbated amyloid pathology. J Neurosci. 2006 Apr 5;26(14):3845-54. PubMed.

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  1. This is a very interesting paper. It indicates that loss of PS1 function may lead to plaque pathology and amyloid depositions. The authors conclude that it is the loss of the γ-secretase function of PS1 and the reduction of Aβ1-40 that lead to increased plaque pathology. Although this conclusion is in agreement with several reports in the last years that presenilin FAD mutations cause a loss (rather than a gain) of γ-secretase function, it is not necessary that the mechanism of plaque pathology in AD involves directly the γ-secretase function. Increased plaque pathology (and even Aβ production) may also result from increased activities in apoptotic pathways that, in turn, may be caused by many factors including a loss of PS1 function in cell survival pathways, a γ-secretase-independent function of PS1 (Baki et al., 2004).

    References:

    . PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J. 2004 Jul 7;23(13):2586-96. PubMed.