The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Hussain, Ishrut; Fabrègue, Julien; Anderes, Laurence; Ousson, Solenne; Borlat, Frédéric; Eligert, Valerie; Berger, Sébastien; Dimitrov, Milen; Alattia, Jean‐René; Fraering, Patrick C.; Beher, Dirk

doi:10.1074/jbc.m112.370924

Cited by 46 publications

(57 citation statements)

References 29 publications

(44 reference statements)

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“…Nonessential factors, such as CD147, TMP21, γ-secretase activating protein (GSAP), β-arrestin-1 β-arrestin-2, Erin-2, syntexin-1, voltage-dependent anion channel 1 (VDAC1), contactin-associated protein 1 (CNTNAP1), TPPP and NDUFS7 have been found to be associated with the γ-secretase complex and modulate γ-secretase activity and specificity; (26, 88–94) however, the functional significance of some of these interactions has been contended. (95, 96) (97) Moreover, γ-secretase has been shown to interact with tetraspanin-enriched microdomains, or lipid rafts. (98) It has been suggested that different γ-secretase complexes can contribute to substrate specificity, (99, 100) which is exemplified by genetic knockout of Aph-1b in a mouse AD model that improved the disease-relevant phenotypic features without Notch-related side effects.…”

Section: γ-Secretase and Aβ Peptidesmentioning

confidence: 99%

Development and Mechanism of γ-Secretase Modulators for Alzheimer’s Disease

2013

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γ-Secretase is an aspartyl intramembranal protease composed of presenilin, Nicastrin, Aph1 and Pen2 with 19 transmembrane domains. γ-Secretase cleaves the amyloid precursor proteins (APP) to release Aβ peptides that likely play a causative role in the pathogenesis of Alzheimer disease (AD). In addition, γ-secretase cleaves Notch and other type I membrane proteins. γ-Secretase inhibitors (GSIs) have been developed and used for clinical studies. However, clinical trials have shown adverse effects of GSIs that are potentially linked with non-discriminatory inhibition of Notch signaling, overall APP processing and other substrate cleavages. Therefore, these findings call for the development of disease modifying agents that target γ-secretase activity to lower Aβ42 production without blocking the overall processing of γ-secretase substrates. γ-Secretase modulators (GSMs) originally derived from non-steroidal anti-inflammatory drugs (NSAIDs) display such characteristics and are the focus of this review. However, first generation GSMs have limited potential due to low potency and undesired neuropharmacokinetic properties. This generation of GSMs has been suggested to interact with the APP substrate, γ-secretase or both. To improve the potency and brain availability, second generation GSMs including NSAID-derived carboxylic acid and non-NSAID-derived heterocyclic chemotypes as well as natural product-derived GSMs have been developed. Animal studies of this generation of GSMs have shown encouraging preclinical profiles. Moreover, using potent GSM photoaffinity probes, multiple studies unambiguously have showed that both carboxylic acid and heterocyclic GSMs specifically target presenilin, the catalytic subunit of γ-secretase. In addition, two types of GSMs have distinct binding sites within the γ-secretase complex and exhibit different Aβ profiles. GSMs induce a conformational change of γ-secretase to achieve modulation. Various models are proposed and discussed. Despite the progress of GSM research, many outstanding issues remain to be investigated to achieve the ultimate goal of developing GSMs as effective AD therapies.

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Section: γ-Secretase and Aβ Peptidesmentioning

confidence: 99%

Development and Mechanism of γ-Secretase Modulators for Alzheimer’s Disease

2013

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“…GSAP is synthetized from a larger 98 kDa protein, previously termed pion homologue protein (PION), which is rapidly processed into the predominant 16 kDa active form [5], resulting in the modulation of γ-secretase-Aβ production by its interaction with presenilin 1 (PS1) and APP-CTF without affecting notch cleavage [5]. In vitro and in vivo studies have demonstrated that changes in GSAP levels regulate Aβ production [5–7]. Studies in transgenic mouse models of AD have shown that pharmacological (using the kinase inhibitor imatinib) or genetic reduction of GSAP leads to a decrease in Aβ production, plaque development and tau phosphorylation [5–7].…”

Section: Introductionmentioning

confidence: 99%

“…In vitro and in vivo studies have demonstrated that changes in GSAP levels regulate Aβ production [5–7]. Studies in transgenic mouse models of AD have shown that pharmacological (using the kinase inhibitor imatinib) or genetic reduction of GSAP leads to a decrease in Aβ production, plaque development and tau phosphorylation [5–7]. GSAP immunoreactivity has been associated with neuronal PS1 and Aβ immunopositive plaques in the frontal cortex and hippocampus in AD [8].…”

Section: Introductionmentioning

confidence: 99%

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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“…Interestingly, in AD brains GSAP immunoreactive deposits are closely associated with Aβ-containing amyloid plaques (15). While conflicting reports on the influence that peripheral GSAP pharmacological blockade may have on Aβ levels (16,17), we recently showed that intra-cerebral injection of imatinib, a GSAP inhibitor, reduced Aβ levels and deposition in the 3xTg mice (18). However, despite its implication in AD pathogenesis the molecular mechanism controlling its expression is unknown.…”

Section: Discussionmentioning

confidence: 95%

Gamma Secretase-Activating Protein Is a Substrate for Caspase-3: Implications for Alzheimer’s Disease

Chu

Joshi

et al. 2015

Biological Psychiatry

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SUMMARY Background A major hallmark feature of Alzheimer’s disease (AD) is the accumulation of amyloid β (Aβ), whose formation is regulated by the γ-secretase complex and its activating protein (also known as GSAP). Because GSAP interacts with the γ-secretase without affecting the cleavage of Notch, it is an ideal target for a viable anti-Aβ therapy. However, despite much interest in this protein, the mechanisms involved in its neurobiology are not known. Methods Post-mortem brain tissues from AD patients, transgenic mouse models of AD and neuronal cells were used to investigate the molecular mechanism involved in GSAP formation and subsequent amyloidogenesis. Results We identify a caspase-3 processing domain in the GSAP sequence and provide experimental evidence that this caspase is essential for GSAP activation and biogenesis of Aβ peptides. Furthermore, we demonstrate that caspase-3-dependent GSAP formation occurs in brains of individuals with AD and two different mouse models of AD, and that the process is biologically relevant since its pharmacological blockade reduces Aβ pathology in vivo. Interpretation Our data by identifying caspase-3 as the endogenous modulator of GSAP and Aβ production establish it as a novel, attractive and viable Aβ lowering therapeutic target for AD.

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The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Cited by 46 publications

References 29 publications

Development and Mechanism of γ-Secretase Modulators for Alzheimer’s Disease

Development and Mechanism of γ-Secretase Modulators for Alzheimer’s Disease

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

Gamma Secretase-Activating Protein Is a Substrate for Caspase-3: Implications for Alzheimer’s Disease

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The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Cited by 46 publications

References 29 publications

Development and Mechanism of γ-Secretase Modulators for Alzheimer’s Disease

Development and Mechanism of γ-Secretase Modulators for Alzheimer’s Disease

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

Gamma Secretase-Activating Protein Is a Substrate for Caspase-3: Implications for Alzheimer’s Disease

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