Insulin-degrading enzyme is not secreted from cultured cells

Song, Eun Suk; Rodgers, David W.; Hersh, Louis B.

doi:10.1038/s41598-018-20597-6

Cited by 20 publications

(18 citation statements)

References 38 publications

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“…Of note, a certain enzymatic activity is detected associated to the presence of IDE protein in EVs, although to the same extent that the intracellular IDE activity displayed by cholesterol-enriched cells exposed to Aβ, which is significantly low compared to untreated cells. Neither IDE presence nor endopeptidase activity is observed in EVs isolated from untreated control cells, in agreement with a recent article that questions the release of IDE in cultured cells [60]. Moreover, and unlike cholesterol-mediated alterations of IDE function, the release of IDE through EVs after cellular cholesterol enrichment does not require Aβ exposure.…”

Section: Discussionsupporting

confidence: 88%

Oxidative inactivation of amyloid beta-degrading proteases by cholesterol-enhanced mitochondrial stress

et al. 2019

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Familial early-onset forms of Alzheimer's disease (AD) are linked to overproduction of amyloid beta (Aβ) peptides, while decreased clearance of Aβ is the driving force leading to its toxic accumulation in late-onset (sporadic) AD. Oxidative modifications and defective function have been reported in Aβ-degrading proteases such as neprilysin (NEP) and insulin-degrading enzyme (IDE). However, the exact mechanisms that regulate the proteolytic clearance of Aβ and its deficits are largely unknown. We have previously showed that cellular cholesterol loading, by depleting the mitochondrial GSH (mGSH) content, stimulates Αβ-induced mitochondrial oxidative stress and promotes AD-like pathology in APP-PSEN1-SREBF2 mice. Here, using the same AD mouse model we examined whether cholesterol-enhanced mitochondrial oxidative stress affects NEP and IDE function. We found that brain extracts from APP-PSEN1-SREBF2 mice displayed increased presence of oxidatively modified forms of NEP and IDE, associated with impaired enzymatic activities. Both alterations were substantially recovered after an in vivo treatment with the cholesterol-lowering agent 2-hydroxypropyl-β-cyclodextrin. The recovery of the proteolytic activity after treatment was accompanied with a significant reduction of Aβ levels. Supporting these results, cholesterol-enriched SH-SY5Y cells were more sensitive to Aβ-induced impairment of IDE and NEP function in vitro . The rise of cellular cholesterol also stimulated the extracellular release of IDE by an unconventional autophagy-coordinated mechanism. Recovery of depleted pool of mGSH in these cells not only prevented the detrimental effect of Aβ on intracellular AβDPs activities but also had an impact on extracellular IDE levels and function, stimulating the extracellular Aβ degrading activity. Therefore, changes in brain cholesterol levels by modifying the mGSH content would play a key role in IDE and NEP-mediated proteolytic elimination of Aβ peptides and AD progression.

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Section: Discussionsupporting

confidence: 88%

Oxidative inactivation of amyloid beta-degrading proteases by cholesterol-enhanced mitochondrial stress

et al. 2019

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“…This process is stimulated by statins which might be a contributory factor in the proposed protection against AD development by statin treatment (Glebov & Walter, ). A recent study has, however, now called into question the significance of IDE secretion from cells suggesting that the presence of extracellular IDE is largely a reflection of a loss in cell integrity (Song, Rodgers, & Hersh, ), and hence, the relevance of IDE to extracellular peptide degradation in vivo may require some reevaluation. Nevertheless, the evidence for a significant involvement of IDE in Aβ clearance in vivo remains strong as does its potential as a therapeutic target in AD prevention.…”

Section: The Key Adesmentioning

confidence: 99%

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Nalivaeva

Turner

2019

British J Pharmacology

135

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Targeting the amyloid‐β (Aβ) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aβ is central to the disease process. Most attention has focused on the biosynthesis of Aβ from its precursor protein through the successive actions of the β‐ and γ‐secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aβ are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid‐degrading enzymes (ADEs) and by a variety of transport processes. The development of late‐onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin‐degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up‐regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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“…According to Yin et al (2006), in addition to NEP, ECE, and IDE, there may be proteases that have yet to be experimentally identified, contributing to astrocytemediated degradation of Aβ, because NEP, ECE, and IDE were undetected with Western blot analysis of conditioned media of neonatal mouse astrocytes. Moreover, it has been reported that cultured cells may be incapable of secreting IDE, and it is still undetermined whether NEP is capable of degrading oligomeric amyloid beta (Saido and Leissring, 2012;Song et al, 2018). There is evidence that estrogen promotes amyloid beta degradation through the induction of NEP (Liang et al, 2010), and there is also evidence that IDE is induced by 17β-estradiol, reducing amyloid beta load in vivo (Zhao et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Medroxyprogesterone Acetate Impairs Amyloid Beta Degradation in a Matrix Metalloproteinase-9 Dependent Manner

Porter

Sarkar

Dakhlallah

et al. 2020

Front. Aging Neurosci.

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Despite the extensive use of hormonal methods as either contraception or menopausal hormone therapy (HT), there is very little known about the potential effects of these compounds on the cellular processes of the brain. Medroxyprogesterone Acetate (MPA) is a progestogen used globally in the hormonal contraceptive, Depo Provera, by women in their reproductive prime and is a major compound found in HT formulations used by menopausal women. MPA promotes changes in the circulating levels of matrix metalloproteinases (MMPs), such as MMP-9, in the endometrium, yet limited literature studying the effects of MPA on neurons and astroglia cells has been conducted. Additionally, the dysregulation of MMPs has been implicated in the pathology of Alzheimer's disease (AD), where inhibiting the secretion of MMP-9 from astroglia reduces the proteolytic degradation of amyloid-beta. Thus, we hypothesize that exposure to MPA disrupts proteolytic degradation of amyloid-beta through the downregulation of MMP-9 expression and subsequent secretion. To assess the effect of progestins on MMP-9 and amyloid-beta, in vitro, C6 rat glial cells were exposed to MPA for 48 h and then the enzymatic, secretory, and amyloid-beta degrading capacity of MMP-9 was assessed from the conditioned culture medium. We found that MPA treatment inhibited transcription of MMP-9, which resulted in a subsequent decrease in the production and secretion of MMP-9 protein, in part through the glucocorticoid receptor. Additionally, we investigated the consequences of amyloid beta-degrading activity and found that MPA treatment decreased proteolytic degradation of amyloid-beta. Our results suggest MPA suppresses amyloid-beta degradation in an MMP-9-dependent manner, in vitro, and potentially compromises the clearance of amyloid-beta in vivo.

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Insulin-degrading enzyme is not secreted from cultured cells

Cited by 20 publications

References 38 publications

Oxidative inactivation of amyloid beta-degrading proteases by cholesterol-enhanced mitochondrial stress

Oxidative inactivation of amyloid beta-degrading proteases by cholesterol-enhanced mitochondrial stress

Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

Medroxyprogesterone Acetate Impairs Amyloid Beta Degradation in a Matrix Metalloproteinase-9 Dependent Manner

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