. Gamma secretase-mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke. Nat Med. 2006 Jun;12(6):621-3. PubMed.

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  1. The paper by Doglio et al. has important implications for both the biological functions of the presenilin (PS) complex and the mechanisms by which PS FAD mutations promote neurodegeneration and other structural abnormalities in AD. The paper verifies previous results that presenilins regulate the PI3K/Akt cell survival pathway through a mechanism that is independent of the γ-secretase activity (Baki et al., 2004). This report is also consistent with recent evidence that FAD mutations may promote cell death and AD-related tau overphosphorylation through a mechanism that involves loss of presenilin function in the PI3K/Akt/GSK3 and other cell signaling pathways (Baki et al., 2004; Kang et al., 2005). This last concept is in contrast to the widely held view that FAD mutations cause a gain of presenilin γ-secretase function thus increasing production of neurotoxic species like Aβ1-42 (see, however, ARF ongoing discussion). The data on Aph-1/aPKC/PAR-1 indicate a new pathway that may also contribute to tau phosphorylation. Clearly, new exciting data emerging in the last two years from several laboratories promote novel concepts not only for the biological functions of PS1, but also for the mechanisms by which presenilin FAD mutations induce the specific neuropathology associated with AD.

    References:

    . gamma-cleavage-independent functions of presenilin, nicastrin, and Aph-1 regulate cell-junction organization and prevent tau toxicity in vivo. Neuron. 2006 May 4;50(3):359-75. PubMed.

    . 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.

    . Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. J Biol Chem. 2005 Sep 9;280(36):31537-47. PubMed.

    View all comments by Nikolaos K. Robakis

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  1. Protease or Not?—More to Presenilin Toxicity than Meets the (Fly's) Eye