Transcriptional Regulation of Insulin-degrading Enzyme Modulates Mitochondrial Amyloid β (Aβ) Peptide Catabolism and Functionality

Leal, María Celeste; Magnani, Natalia; Villordo, Sergio; Marino-Buslje, Cristina; Evelson, Pablo; Castaño, Eduardo M.; Morelli, Laura

doi:10.1074/jbc.m112.424820

Cited by 32 publications

(30 citation statements)

References 60 publications

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“…The original observation that IDE was able to hydrolyse Aβ in vitro (Kurochkin & Goto, 1994; for review, see Kurochkin, Guarnera, & Berezovsky, 2018) was extended by Selkoe and colleagues to demonstrate that a microglial cell line secreted a metalloprotease immunologically identical to IDE, which was able to regulate extracellular levels of Aβ (Qiu et al, 1998). IDE also protects mitochondria against Aβ accumulation and dysfunction (Leal et al, 2013). Since that time, IDE has been regarded as a significant contributor to Aβ degradation both in vitro and in vivo.…”

Section: Insulin-degrading Enzyme (Insulysin)mentioning

confidence: 99%

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

Nalivaeva

Turner

2019

British J Pharmacology

134

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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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Section: Insulin-degrading Enzyme (Insulysin)mentioning

confidence: 99%

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

Nalivaeva

Turner

2019

British J Pharmacology

134

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“…RNA from iAb containing neurons obtained by LCM was isolated with PicoPure RNA Isolation Kit (Applied Biosystems) and from hippocampal homogenates, a standard protocol was used. 7 RNA quality control and quantification were performed with a bioanalyzer (Agilent 2100). Samples with a RIN (RNA Integrity Number) value lower than 6 were discarded as indicative of degraded RNA.…”

Section: Evaluation Of Energy Metabolism and A Catabolism Genes Exprementioning

confidence: 99%

Synaptosomal bioenergetic defects are associated with cognitive impairment in a transgenic rat model of early Alzheimer's disease

Adami

Quijano

Magnani

et al. 2016

J Cereb Blood Flow Metab

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Synaptic bioenergetic deficiencies may be associated with early Alzheimer's disease (AD). To explore this concept, we assessed pre-synaptic mitochondrial function in hemizygous (+/-)TgMcGill-R-Thy1-APP rats. The low burden of Aβ and the wide array of behavioral and cognitive impairments described in 6-month-old hemizygous TgMcGill-R-Thy1-APP rats (Tg(+/-)) support their use to investigate synaptic bioenergetics deficiencies described in subjects with early Alzheimer's disease (AD). In this report, we show that pre-synaptic mitochondria from Tg(+/-) rats evidence a decreased respiratory control ratio and spare respiratory capacity associated with deficits in complex I enzymatic activity. Cognitive impairments were prevented and bioenergetic deficits partially reversed when Tg(+/-) rats were fed a nutritionally complete diet from weaning to 6-month-old supplemented with pyrroloquinoline quinone, a mitochondrial biogenesis stimulator with antioxidant and neuroprotective effects. These results provide evidence that, as described in AD brain and not proven in Tg mice models with AD-like phenotype, the mitochondrial bioenergetic capacity of synaptosomes is not conserved in the Tg(+/-) rats. This animal model may be suitable for understanding the basic biochemical mechanisms involved in early AD.

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“…In AD brain, IDE has a unique distribution with higher levels, being more oxidized in the cerebellum than in the hippocampus (Caccamo et al, 2005). Various in vitro studies and animal models reveal that impairment of Aβ degradation occurs in the brain due to deficit in IDE function (Leal et al, 2013) and vice versa. The overexpression of IDE reduces Aβ levels and attenuates or completely prevents amyloid plaque formation in the brain.…”

Section: Insulin Degrading Enzyme (Ide)mentioning

confidence: 99%