. Phosphoinositides suppress gamma-secretase in both the detergent-soluble and -insoluble states. J Biol Chem. 2008 Jul 11;283(28):19283-92. PubMed.

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  1. Comment by Tae-Wan Kim, Laura Beth McIntire, Min Suk Kang, and Gilbert Di Paolo
    Our previous study reported that the levels of secreted Aβ42 were found to inversely correlate with the levels of phosphatidylinositol-4,5-bisphosphate, also known as PI(4,5)P2 (see Landman et al., 2006). For instance, Aβ42 production is decreased in cells with elevated PI(4,5)P2 levels (e.g., cells treated with edelfosine, a phospholipase C inhibitor), while Aβ42 levels are increased in cells with lower PI(4,5)P2 levels (e.g., cells overexpressing synaptojanin 1, a PI(4,5)P2 5-phosphatase).

    This elegant biochemical study by Yasuo Ihara and colleagues provides further insight into how alterations in the lipid composition of the membrane could influence the activity of the membrane-embedded γ-secretase complex. The authors found that PI(4,5)P2 directly influences the activity of γ-secretase using cell-free assays. PI(4,5)P2 was shown to competitively inhibit γ-secretase activity by suppressing the association of the γ-secretase complex with the substrate. Thus, this study provides the underlying mechanism of PI(4,5)P2-dependent regulation of γ-secretase activity.

    In the cell-free assays, PI(4,5)P2 was found to inhibit Aβ42, Aβ40, and AICD production. In contrast, Landman et al., found that Aβ42 was the major product affected by treatment with PI(4,5)P2-modulating agents in intact cells. This may be attributed to the fact that PI(4,5)P2 is unevenly distributed in the cells (see Di Paolo and De Camilli, 2006) and PI(4,5)P2 changes may only affect a portion of the γ-secretase activity in the cells. This idea is supported by the fact that different subcellular sites contribute to the differences in cleavage characteristics of the γ-secretase (see Fukumori et al., 2006).

    Besides its regulatory role in γ-secretase activity, a pool of PI(4,5)P2 is involved in the synaptic dysfunction triggered by oligomeric forms of Aβ (see Berman et al., 2008). Thus, enzymatic modulators of the level or stability of PI(4,5)P2 emerge as novel therapeutic targets for potential AD therapeutics.

    References:

    . Oligomeric amyloid-beta peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism. Nat Neurosci. 2008 May;11(5):547-54. PubMed.

    . Phosphoinositides in cell regulation and membrane dynamics. Nature. 2006 Oct 12;443(7112) PubMed.

    . Presenilin-dependent gamma-secretase on plasma membrane and endosomes is functionally distinct. Biochemistry. 2006 Apr 18;45(15):4907-14. PubMed.

    . Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism. Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19524-9. PubMed.