Ammonia induces amyloidogenesis in astrocytes by promoting amyloid precursor protein translocation into the endoplasmic reticulum

Komatsu, Ayaka; Iida, Ikuo; Nasu, Yusuke; Ito, Genki; Harada, Fumiko; Kishikawa, Sari; Moss, Stephen J.; Maeda, Takeyasu; Terunuma, Miho

doi:10.1016/j.jbc.2022.101933

Cited by 9 publications

(8 citation statements)

References 63 publications

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“…52 Furthermore, the expression of GFAP proteins in the brain tissue of swine models of HE was decreased and astroglial cells changed morphologically. 53 On the contrary, in other studies, GFAP immunoreactivity was significantly increased in hippocampal areas of thioacetamide-induced HE rats 54,55 and cerebral cortex of hyperammonemic rats, 56 whereas in BDL-induced cirrhosis and HE rats, opposite results were seen. 55 Ammonia on organotypic mice brain slice increased expression of GFAP and caused astrocyte swelling.…”

Section: Discussionmentioning

confidence: 72%

New Insight Into Mechanisms of Hepatic Encephalopathy: An Integrative Analysis Approach to Identify Molecular Markers and Therapeutic Targets

Sepehrinezhad

Shahbazi

Negah

et al. 2023

Bioinform Biol Insights

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Hepatic encephalopathy (HE) is a set of complex neurological complications that arise from advanced liver disease. The precise molecular and cellular mechanism of HE is not fully understood. Differentially expressed genes (DEGs) from microarray technologies are powerful approaches to obtain new insight into the pathophysiology of HE. We analyzed microarray data sets of cirrhotic patients with HE from Gene Expression Omnibus to identify DEGs in postmortem cerebral tissues. Consequently, we uploaded significant DEGs into the STRING to specify protein-protein interactions. Cytoscape was used to reconstruct the genetic network and identify hub genes. Target genes were uploaded to different databases to perform comprehensive enrichment analysis and repurpose new therapeutic options for HE. A total of 457 DEGs were identified in 2 data sets totally from 12 cirrhotic patients with HE compared with 12 healthy subjects. We found that 274 genes were upregulated and 183 genes were downregulated. Network analyses on significant DEGs indicated 12 hub genes associated with HE. Enrichment analysis identified fatty acid beta-oxidation, cerebral organic acidurias, and regulation of actin cytoskeleton as main involved pathways associated with upregulated genes; serotonin receptor 2 and ELK-SRF/GATA4 signaling, GPCRs, class A rhodopsin-like, and p38 MAPK signaling pathway were related to downregulated genes. Finally, we predicted 39 probable effective drugs/agents for HE. This study not only confirms main important involved mechanisms of HE but also reveals some yet unknown activated molecular and cellular pathways in human HE. In addition, new targets were identified that could be of value in the future study of HE.

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Section: Discussionmentioning

confidence: 72%

New Insight Into Mechanisms of Hepatic Encephalopathy: An Integrative Analysis Approach to Identify Molecular Markers and Therapeutic Targets

Sepehrinezhad

Shahbazi

Negah

et al. 2023

Bioinform Biol Insights

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“…Endocytosis is a cellular response to a multitude of stress conditions that allows organisms to tolerate complicated conditions by shutting down external signaling [44]. Similar physiological changes have been widely identified in mammals and fungal cells such as Aspergillus nidulans and yeast [45-47]. We also previously described that ammonia induces trap formation by regulating endocytosis through arrestin-GPCR signaling [27].…”

Section: Discussionmentioning

confidence: 94%

ESCRT pathway-dependent MVBs contribute to the morphogenesis of the fungusArthrobotrys oligospora

Tian

Huang

Cui

et al. 2022

Preprint

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Ammonia opens trap formation in the nematode-trapping (NT) fungus Arthrobotrys oligospora, an intriguing morphological switch in NT fungi, where saprophytic mycelia are converted to pathogenic organs. Endocytosis plays a prominent role in nutrient uptake, signaling cascades, and maintenance of cellular homeostasis in higher eukaryotes. Here, we demonstrate that ammonia efficiently promotes endocytosis via the formation of 3D-adhesive mycelial nets in A. oligospora. Trap production is followed by the presence of massive multivesicular bodies (MVBs) and membrane rupture and repair. Additionally, both the ubiquitin-proteasome system and the endosomal sorting complex for transport (ESCRT) pathway are immediately linked to endocytosis regulation and MVB formation in ammonia-induced trap formation. Moreover, disruption of the ESCRT-1 complex subunit proteins AoHse and AoVps27 led to the complete loss of membrane endocytosis and trap formation. Finally, the deletion of the deubiquitinase AoSst2 caused a significant reduction in the number of trap structures produced in response to exposure to ammonia or nematodes. Overall, our results increase our knowledge of the molecular mechanisms underlying the phenotypic changes in the NT fungal group, demonstrating that the endocytosis-ESCRT-MVB pathway participates in the regulation of trapping organs.

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“…36 Treatment with cytokines such as interleukin-1 (IL-1), [36][37][38][39][40] tumor necrosis factor β (TNFβ), 38,39,41 tumor necrosis factor α (TNFα) 36 and interferon γ (IFNγ) 36,37 increased APP levels in astrocytes both in vitro and in vivo. Astrocytic APP levels increase also in response to many pathological conditions including ischemia, 42 brain trauma 43,44 heat shock, 45 cuprizone-induced demyelination, 46 quinolinic acid excitotoxicity 47 and hyperammonaemia 48,49 as well as following increase in cytoplasmic cyclic adenosine monophosphate (cAMP). 50 In all these conditions, astrocytes generate molecules involved in inflammation including cytokines.…”

Section: Introductionmentioning

confidence: 99%

Amyloid precursor protein induces reactive astrogliosis

Velezmoro Jauregui,

Vukić,

Onyango

et al. 2024

Acta Physiologica

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AimAstrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis.MethodsWe investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP‐deficient astrocytes in response to APP and well‐established stressors.ResultsOverexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN‐stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI.ConclusionsThe APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis.

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Ammonia induces amyloidogenesis in astrocytes by promoting amyloid precursor protein translocation into the endoplasmic reticulum

Cited by 9 publications

References 63 publications

New Insight Into Mechanisms of Hepatic Encephalopathy: An Integrative Analysis Approach to Identify Molecular Markers and Therapeutic Targets

New Insight Into Mechanisms of Hepatic Encephalopathy: An Integrative Analysis Approach to Identify Molecular Markers and Therapeutic Targets

ESCRT pathway-dependent MVBs contribute to the morphogenesis of the fungusArthrobotrys oligospora

Amyloid precursor protein induces reactive astrogliosis

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