Phosphoinositides Suppress -Secretase in Both the Detergent-soluble and -insoluble States

Department of Neuropathology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-0033, Japan.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2008; 283(28):19283-92. DOI: 10.1074/jbc.M705954200
Source: PubMed


γ-Secretase is an aspartic protease that hydrolyzes type I membrane proteins within the hydrophobic environment of the lipid
bilayer. Using the CHAPSO-solubilized γ-secretase assay system, we previously found that γ-secretase activity was sensitive
to the concentrations of detergent and phosphatidylcholine. This strongly suggests that the composition of the lipid bilayer
has a significant impact on the activity of γ-secretase. Recently, level of secreted β-amyloid protein was reported to be
attenuated by increasing levels of phosphatidylinositol 4,5-diphosphate (PI(4,5)P2) in cultured cells. However, it is not clear whether PI(4,5)P2 has a direct effect on γ-secretase activity. In this study, we found that phosphoinositides directly inhibited CHAPSO-solubilized
γ-secretase activity. Interestingly, neither phosphatidylinositol nor inositol triphosphate altered γ-secretase activity.
PI(4,5)P2 was also found to inhibit γ-secretase activity in CHAPSO-insoluble membrane microdomains (rafts). Kinetic analysis of β-amyloid
protein production in the presence of PI(4,5)P2 suggested a competitive inhibition. Even though phosphoinositides are minor phospholipids of the membrane, the concentration
of PI(4,5)P2 within the intact membrane has been reported to be in the range of 4–8 mm. The presence of PI(4,5)P2-rich rafts in the membrane has been reported in a range of cell types. Furthermore, γ-secretase is enriched in rafts. Taking
these data together, we propose that phosphoinositides potentially regulate γ-secretase activity by suppressing its association
with the substrate.

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    • "In the presence of PI (4, 5) P 2 , the activity of γ-secretase is strongly inhibited. This inhibitory effect on APP cleavage was proposed to reflect competitive binding between PI (4, 5) P 2 and APP fragment for the γ-secretase complex (Osawa et al., 2008; Osenkowski et al., 2008). These studies indicate that PI (4, 5) P 2 negatively regulate Aβ production via inhibiting the activity of γ-secretase complex. "
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    ABSTRACT: Lipids serve many distinct functions in cellular homeostasis such as membrane organization, as a platform for membrane function and protein/protein or protein/lipid interaction, energy storage, as well as secondary messengers in signal transduction. Perturbations in lipid homeostasis may result in abnormal cellular function. Alzheimer's disease (AD) is a neurodegenerative disorder in which the brain represents the primary site of pathology. While there is a plethora of previous work pertaining to AD pathogenesis, the precise mechanism of the disease is still not well-understood. Recent wave of technological advances in the realm of lipidomics has enabled scientists to look at AD pathogenesis from a previously unexplored perspective, and studies have revealed extensive lipid aberrations are implicated in the disease pathology. Herein, we review the critical lipids alternations, which affect amyloid plaque and neurofibrillary tangles formation and accumulation, as well as lipid aberrations related to neuronal and synaptic dysfunction in cells and animal models. We also summarise lipid abnormalities observed in the human cerebrospinal fluid (CSF), as well as other circulating fluids including plasma and serum in association with AD, which could serve as candidate biomarkers to diagnose and monitor the disease.
    Biological Chemistry 09/2015; 396(12). DOI:10.1515/hsz-2015-0207 · 3.27 Impact Factor
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    • "Yet, to date, biological significance of the astonishing number of potentially unique PIs and PIPxs is unknown. This is primarily due to the challenges associated with unambiguous compositional identification of PIs and PIPxs in biological membranes [1, 15–19]. "
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    ABSTRACT: The capacity to predict and visualize all theoretically possible glycerophospholipid molecular identities present in lipidomic datasets is currently limited. To address this issue, we expanded the search-engine and compositional databases of the online Visualization and Phospholipid Identification (VaLID) bioinformatic tool to include the glycerophosphoinositol superfamily. VaLID v1.0.0 originally allowed exact and average mass libraries of 736,584 individual species from eight phospholipid classes: glycerophosphates, glyceropyrophosphates, glycerophosphocholines, glycerophosphoethanolamines, glycerophosphoglycerols, glycerophosphoglycerophosphates, glycerophosphoserines, and cytidine 5'-diphosphate 1,2-diacyl-sn-glycerols to be searched for any mass to charge value (with adjustable tolerance levels) under a variety of mass spectrometry conditions. Here, we describe an update that now includes all possible glycerophosphoinositols, glycerophosphoinositol monophosphates, glycerophosphoinositol bisphosphates, and glycerophosphoinositol trisphosphates. This update expands the total number of lipid species represented in the VaLID v2.0.0 database to 1,473,168 phospholipids. Each phospholipid can be generated in skeletal representation. A subset of species curated by the Canadian Institutes of Health Research Training Program in Neurodegenerative Lipidomics (CTPNL) team is provided as an array of high-resolution structures. VaLID is freely available and responds to all users through the CTPNL resources web site.
    02/2014; 2014(8):818670. DOI:10.1155/2014/818670
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    • "However, as membrane thickness differs between distinct subcellular compartments, these characteristics of different membrane systems could strongly affect the generation of different Aβ species. Inhibitory effects on purified γ-secretase were observed for phosphoinosites [126] and plasmalogens [127]. From the phosphatidylinositols tested, phosphatidylinositol(4,5)bisphosphate was most potent in γ-secretase inhibition, while phosphatidylinositol and phosphatidylinositol(3,4,5)trisphosphate had negligible effects. "
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    ABSTRACT: Alzheimer’s disease (AD) is neuropathologically characterized by the combined occurrence of extracellular β-amyloid plaques and intracellular neurofibrillary tangles in the brain. While plaques contain aggregated forms of the amyloid β-peptide (Aβ), tangles are formed by fibrillar forms of the microtubule associated protein tau. All mutations identified so far to cause familial forms of early onset AD (FAD) are localized close to or within the Aβ domain of the amyloid precursor protein (APP) or in the presenilin proteins that are essential components of a protease complex involved in the generation of Aβ. Mutations in the tau gene are not associated with FAD, but can cause other forms of dementia. The genetics of FAD together with biochemical and cell biological data, led to the formulation of the amyloid hypothesis, stating that accumulation and aggregation of Aβ is the primary event in the pathogenesis of AD, while tau might mediate its toxicity and neurodegeneration. The generation of Aβ involves sequential proteolytic cleavages of the amyloid precursor protein (APP) by enzymes called β-and γ-secretases. Notably, APP itself as well as the secretases are integral membrane proteins. Thus, it is very likely that membrane lipids are involved in the regulation of subcellular transport, activity, and metabolism of AD related proteins. Indeed, several studies indicate that membrane lipids, including cholesterol and sphingolipids (SLs) affect Aβ generation and aggregation. Interestingly, APP and other AD associated proteins, including β-and γ-secretases can, in turn, influence lipid metabolic pathways. Here, we review the close connection of cellular lipid metabolism and AD associated proteins and discuss potential mechanisms that could contribute to initiation and progression of AD.
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