Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence

Chu, Jin; Li, Jianguo; Hoffman, Nicholas E.; Stough, Alexandra M.; Madesh, Muniswamy; Praticò, Domenico

doi:10.1038/srep11086

Cited by 9 publications

(15 citation statements)

References 25 publications

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“…Conversely, a recent report using frontal cortex from a small number of individuals (7 AD and 4 controls) showed an increase in the levels of the active, but not full-length GSAP [22]. The discrepancies between these findings and ours may be related to differences in methodologies, study design and/or cohorts examined.…”

Section: Discussioncontrasting

confidence: 84%

“…Interestingly, levels of the full-length 98 kDa and active 16 kDa GSAP forms were significantly increased in the frontal cortex of patients with Down Syndrome (DS) compared age-matched controls [9]. The discrepancy in 16 kDa GSAP levels between DS and AD (present findings) could be related to the presence of an extra copy of the APP gene in DS that might stimulate the expression of GSAP or other confounding components such as transcription factors [9, 22]. Data indicate that formation of the 16 kDa GSAP active form depends on caspase-3 [9], an apoptotic marker that is elevated and highly expressed in neurofibrillary tangles and plaques, in both human AD and animal models of this disease [21].…”

Section: Discussionmentioning

confidence: 88%

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Frontal Cortex and Hippocampal γ-Secretase Activating Protein Levels in Prodromal Alzheimer Disease

et al. 2017

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Background: β-Amyloid (Aβ) is the product of concerted cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, the molecular mechanisms that regulate this process are not well understood. Recently, evidence was reported that γ-secretase activating protein (GSAP, 16 kDa), derived from a larger precursor protein (98 kDa), plays a role in Aβ metabolism through a mechanism involving its interaction with both γ-secretase and APP. However, a detailed evaluation of GSAP protein levels and their association with clinical and neuropathological variables are lacking during the clinical progression of Alzheimer disease (AD). Methods: We quantified levels of the GSAP precursor (98 kDa) and its active form (16 kDa) in the frontal cortex and hippocampus, areas displaying extensive Aβ and neurofibrillary tangle (NFT) pathology, in subjects who came to autopsy with a premortem clinical diagnosis of noncognitive impairment, mild cognitive impairment, mild to moderate AD, and severe AD using Western blotting. Results: Analysis found that 98-kDa GSAP levels were increased, while those of 16 kDa were reduced in the frontal cortex of severe-AD subjects. By contrast, GSAP levels remained stable in the hippocampus. Frontal cortex and hippocampal GSAP 98- and 16-kDa levels were not associated with Aβ, NFT, and neuropathological criteria across clinical groups. Interestingly, only neocortical 98-kDa GSAP values showed a significant correlation with the Mini-Mental State Examination and episodic memory scores. Conclusions: These data demonstrate that GSAP proteins are differentially dysregulated in severe AD, but only the full-length form was associated with cognitive test scores in AD.

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Section: Discussioncontrasting

confidence: 84%

Section: Discussionmentioning

confidence: 88%

Frontal Cortex and Hippocampal γ-Secretase Activating Protein Levels in Prodromal Alzheimer Disease

et al. 2017

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“…5-LO generates bioactive lipid mediators that are involved in inflammatory and allergic reactions as well as in autoimmune diseases, and in fact, vitamin E intake has long been associated with the regulation of related diseases, including asthma, cardiovascular diseases, and Alzheimer’s disease 1 , 2 , 45 . Moreover, LT formation in PMNL supports lung colonization of metastasis-initiating breast cancer cells in mouse models 12 , providing a mechanistic basis for the well-established pro-tumor properties of 5-LO 18 .…”

Section: Discussionmentioning

confidence: 99%

Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase

Pein¹,

Ville²,

Pace³

et al. 2018

Nat Commun

116

139

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Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13′-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8–49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13′-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13′-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.

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“…CREB has been demonstrated to control expression of all four members of the γ-secretase complex: APH-1, nicastrin, Pen-2 and PS-1. The effect of 5-LOX on amyloidogenesis may be also related to formation of γ-secretase-activating protein (GSAP) [ 91 ]. GSAP is a crucial molecule responsible for Aβ production by interacting with the γ-secretase complex.…”

Section: -Lipoxygenase and Its Role In Admentioning

confidence: 99%

The Lipoxygenases: Their Regulation and Implication in Alzheimer’s Disease

et al. 2015

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Inflammatory processes and alterations of lipid metabolism play a crucial role in Alzheimer’s disease (AD) and other neurodegenerative disorders. Polyunsaturated fatty acids (PUFA) metabolism impaired by cyclooxygenases (COX-1, COX-2), which are responsible for formation of several eicosanoids, and by lipoxygenases (LOXs) that catalyze the addition of oxygen to linolenic, arachidonic (AA), and docosahexaenoic acids (DHA) and other PUFA leading to formation of bioactive lipids, significantly affects the course of neurodegenerative diseases. Among several isoforms, 5-LOX and 12/15-LOX are especially important in neuroinflammation/neurodegeneration. These two LOXs are regulated by substrate concentration and availability, and by phosphorylation/dephosphorylation through protein kinases PKA, PKC and MAP-kinases, including ERK1/ERK2 and p38. The protein/protein interaction also is involved in the mechanism of 5-LOX regulation through FLAP protein and coactosin-like protein. Moreover, non-heme iron and calcium ions are potent regulators of LOXs. The enzyme activity significantly depends on the cell redox state and is differently regulated by various signaling pathways. 5-LOX and 12/15-LOX convert linolenic acid, AA, and DHA into several bioactive compounds e.g. hydroperoxyeicosatetraenoic acids (5-HPETE, 12S-HPETE, 15S-HPETE), which are reduced to corresponding HETE compounds. These enzymes synthesize several bioactive lipids, e.g. leucotrienes, lipoxins, hepoxilins and docosahexaenoids. 15-LOX is responsible for DHA metabolism into neuroprotectin D1 (NPD1) with significant antiapoptotic properties which is down-regulated in AD. In this review, the regulation and impact of 5-LOX and 12/15-LOX in the pathomechanism of AD is discussed. Moreover, we describe the role of several products of LOXs, which may have significant pro- or anti-inflammatory activity in AD, and the cytoprotective effects of LOX inhibitors.

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Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence

Cited by 9 publications

References 25 publications

Frontal Cortex and Hippocampal γ-Secretase Activating Protein Levels in Prodromal Alzheimer Disease

Frontal Cortex and Hippocampal γ-Secretase Activating Protein Levels in Prodromal Alzheimer Disease

Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase

The Lipoxygenases: Their Regulation and Implication in Alzheimer’s Disease

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Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence

Cited by 9 publications

References 25 publications

Frontal Cortex and Hippocampal &#x03B3;-Secretase Activating Protein Levels in Prodromal Alzheimer Disease

Frontal Cortex and Hippocampal &#x03B3;-Secretase Activating Protein Levels in Prodromal Alzheimer Disease

Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase

The Lipoxygenases: Their Regulation and Implication in Alzheimer’s Disease

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Product

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Frontal Cortex and Hippocampal γ-Secretase Activating Protein Levels in Prodromal Alzheimer Disease

Frontal Cortex and Hippocampal γ-Secretase Activating Protein Levels in Prodromal Alzheimer Disease