Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes

Yang, Hongyan; Wang, Yanlin; Kar, Satyabrata

doi:10.1002/glia.23191

Cited by 15 publications

(27 citation statements)

References 79 publications

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“…Intriguingly, both membrane proteases, TMPRSS2 and ADAM17, partition primarily to the detergent‐resistant membrane domains, that is, lipid rafts of the plasma membrane 13,37 . While no formal evaluation for the expression and/or activity level of TMPRSS2 has been reported in NPC, it is suggested that the plasma membrane levels of ADAM17 are elevated in NPC, 38‐40 presumably due to the previously mentioned NPC‐related alterations in lipid rafts. As a result, it is possible to speculate that this elevated level of ADAM17 in the plasma membrane of NPC cells increases ACE2 shedding and counteracts TMPRSS2‐mediated entry‐favoring modifications, which grants these cells an increased “protection” against the viral binding.…”

Section: Npc‐related Perturbations In Ace2 and Adam17 Interfere With mentioning

confidence: 99%

The lysosome: A potential juncture between SARS‐CoV‐2 infectivity and Niemann‐Pick disease type C, with therapeutic implications

et al. 2020

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Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID‐19. By describing the life cycle of the newly emergent coronavirus, SARS‐CoV‐2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID‐19. Moreover, we propose that Niemann‐Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS‐CoV‐2, by highlighting key established features of the disorder that together result in an “unfavorable” host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID‐19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC‐like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID‐19.

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Section: Npc‐related Perturbations In Ace2 and Adam17 Interfere With mentioning

confidence: 99%

The lysosome: A potential juncture between SARS‐CoV‐2 infectivity and Niemann‐Pick disease type C, with therapeutic implications

et al. 2020

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“…In line with these effects of increased cholesterol in lysosomes, extraction with 2-hydroxypropyl-cyclodextrin (CDX) in AD models revealed a dual effect of CDX in modulating the mechanisms involved in AD pathology (Yang et al, 2017a ). While CDX enhanced lysosomal activity, it impaired autophagosome-lysosome fusion resulting in defective autophagy and clearance of Aβ fragments (Yang et al, 2017b ). Together, these findings strongly suggest that unlike NPC disease, the accumulation of cholesterol in lysosomes does not seem to be a characteristic feature of AD and that prolonged treatment with CDX should be carefully evaluated to avoid unwanted effects on autophagy.…”

Section: Role Of Intracellular Cholesterol In Neurodegenerationmentioning

confidence: 99%

Intracellular Cholesterol Trafficking and Impact in Neurodegeneration

Arenas

Garcı́a-Ruiz

Fernández-Checa

2017

Front. Mol. Neurosci.

113

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Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Particularly enriched in brain, cholesterol homeostasis in this organ is singular with respect to other tissues and exhibits a heterogeneous regulation in distinct brain cell populations. Due to the key role of cholesterol in brain physiology and function, alterations in cholesterol homeostasis and levels have been linked to brain diseases and neurodegeneration. In the case of Alzheimer disease (AD), however, this association remains unclear with evidence indicating that either increased or decreased total brain cholesterol levels contribute to this major neurodegenerative disease. Here, rather than analyzing the role of total cholesterol levels in neurodegeneration, we focus on the contribution of intracellular cholesterol pools, particularly in endolysosomes and mitochondria through its trafficking via specialized membrane domains delineated by the contacts between endoplasmic reticulum and mitochondria, in the onset of prevalent neurodegenerative diseases such as AD, Parkinson disease, and Huntington disease as well as in lysosomal disorders like Niemann-Pick type C disease. We dissect molecular events associated with intracellular cholesterol accumulation, especially in mitochondria, an event that results in impaired mitochondrial antioxidant defense and function. A better understanding of the mechanisms involved in the distribution of cholesterol in intracellular compartments may shed light on the role of cholesterol homeostasis disruption in neurodegeneration and may pave the way for specific intervention opportunities.

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“…Exocytosis of APP fragments generated at the endolysosomal compartments could either be a constitutive process or a consequence of intracellular accumulation due to impaired lysosomal degradation. Cholesterol sequestration by endolysosomes corresponds to decreased lysosomal clearance of APP fragments [ 60 ]. Lysosomal dysfunction is often linked with diminished autophagic flux, which is manifested in astrocytes expressing ApoE4 and correlates with accumulation of Aβ plaque [ 61 ], potentially exacerbating neuronal pathology.…”

Section: Amyloid Precursor Protein and Apoe Cross Paths In Endolysmentioning

confidence: 99%

Endosomal-Lysosomal Processing of Neurodegeneration-Associated Proteins in Astrocytes

Wong

2020

IJMS

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Most common neurodegenerative diseases (NDs) are characterized by deposition of protein aggregates that are resulted from misfolding, dysregulated trafficking, and compromised proteolytic degradation. These proteins exert cellular toxicity to a broad range of brain cells and are found in both neurons and glia. Extracellular monomeric and oligomeric ND-associated proteins are taken up by astrocytes, the most abundant glial cell in the brain. Internalization, intracellular trafficking, processing, and disposal of these proteins are executed by the endosomal-lysosomal system of astrocytes. Endosomal-lysosomal organelles thus mediate the cellular impact and metabolic fate of these toxic protein species. Given the indispensable role of astrocytes in brain metabolic homeostasis, the endosomal-lysosomal processing of these proteins plays a fundamental role in altering the trajectory of neurodegeneration. This review aims at summarizing the mounting evidence that has established the essential role of astrocytic endosomal-lysosomal organelles in the processing of amyloid precursor proteins, Apolipoprotein E (ApoE), tau, alpha synuclein, and huntingtin, which are associated with NDs such as Alzheimer’s, Parkinson’s, and Huntington diseases.

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Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes

Cited by 15 publications

References 79 publications

The lysosome: A potential juncture between SARS‐CoV‐2 infectivity and Niemann‐Pick disease type C, with therapeutic implications

The lysosome: A potential juncture between SARS‐CoV‐2 infectivity and Niemann‐Pick disease type C, with therapeutic implications

Intracellular Cholesterol Trafficking and Impact in Neurodegeneration

Endosomal-Lysosomal Processing of Neurodegeneration-Associated Proteins in Astrocytes

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