Neprilysin and Amyloid Beta Peptide Degradation

Hersh, Louis B.; Rodgers, David W.

doi:10.2174/156720508783954703

Cited by 108 publications

(68 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is consistent with the membrane surface land presynaptic terminal localization of neprilysin (49,63). However, insulin-and IGF-1-induced ADDL reduction was blocked only by phenanthroline, suggesting that the effects of insulin and IGF-1 on ADDL reduction in the medium are mediated by IDE.…”

Section: Expressions Of Ir and Igf-1r Confer On Cells The Capability supporting

confidence: 84%

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Zhao

Lacor

Chen

et al. 2009

Journal of Biological Chemistry

138

101

View full text Add to dashboard Cite

Accumulation of amyloid ␤ (A␤) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of A␤. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied A␤ oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to A␤ aggregation and subsequent synaptic loss.Abnormal protein misfolding and aggregation are common features in neurodegenerative diseases such as Alzheimer (AD), 2 Parkinson, Huntington, and prion diseases (1-3). In the AD brain, intracellular accumulation of hyperphosphorylated Tau aggregates and extracellular amyloid deposits comprise the two major pathological hallmarks of the disease (1, 4). A␤ aggregation has been shown to initiate from A␤1-42, a peptide normally cleaved from the amyloid precursor protein (APP) via activities of ␣-and ␥-secretases (5, 6). A large body of evidence in the past decade has indicated that accumulated soluble oligomers of A␤1-42, likely the earliest or intermediate forms of A␤ deposition, are potently toxic to neurons. The toxic effects of A␤ oligomers include synaptic structural deterioration (7,8) and functional deficits such as inhibition of synaptic transmission (9) and synaptic plasticity (10 -13), as well as memory loss (11,14,15). Accumulation of high levels of these oligomers may also trigger inflammatory processes and oxidative stress in the brain probably due to activation of astrocytes and microglia (16,17). Thus, to understand how a physiologically produced peptide becomes a misfolded toxin has been one of the key issues in uncovering the molecular pathogenesis of the disease.A␤ accumulation and aggregation could derive from overproduction or impaired clearance. Mutations of APP or presenilins 1 and 2, for example, are shown to cause overproduction of A␤1-42 and amyloid deposits in the brain of early onset AD (18,19). Because early onset AD accounts for less than 5% of entire AD population, APP and presenilin mutati...

show abstract

Section: Expressions Of Ir and Igf-1r Confer On Cells The Capability supporting

confidence: 84%

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Zhao

Lacor

Chen

et al. 2009

Journal of Biological Chemistry

138

101

View full text Add to dashboard Cite

show abstract

“…For example, NEP cytoplasmic tail directly associates with the tumor suppressor PTEN, leading to a negative regulation of downstream cell growth and cell survival pathways, thereby regulating Akt/PKB signaling (Sumitomo et al, 2004). In vitro and in vivo evidences show NEP involvement in b-amyloid (bA) catabolism and NEP is now considered one of the most important proteases targeting bA in the extracellular space, raising the concept of its use as therapeutic target for Alzheimer's disease (Hersh and Rodgers, 2008;Iwata et al, 2000;Kanemitsu et al, 2003).…”

Section: M13 Familymentioning

confidence: 99%

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Sbardella

Fasciglione

Gioia

et al. 2012

Molecular Aspects of Medicine

208

212

View full text Add to dashboard Cite

a b s t r a c tHuman matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn 2+ atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes.

show abstract

“…Neprilysin is also known as a neutral endopeptide that has been implicated in the catabolism of amyloid beta peptides in the brain, which has attracted considerable attention, particularly as a potential therapeutic target for Alzheimer's disease (Hersh, Rodgers, 2008). Arteannuin extenuates amyloidogenesis and neuroinflammation in APPswe/PS1De9 transgenic mice via inhibition of nuclear factor-κB and NLRP3 inflammasome activation (Shi et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Identification of neprilysin as a potential target of arteannuin using computational drug repositioning

Ling

Chen

2017

Braz. J. Pharm. Sci.

View full text Add to dashboard Cite

The discovery of arteannuin (qinghaosu) in the 20 th Century was a major advance for medicine. Besides functioning as a malaria therapy, arteannuin is a pharmacological agent in a range of other diseases, but its mechanism of action remains obscure. In this study, the reverse docking server PharmMapper was used to identify potential targets of arteannuin. The results were checked using the chemical-protein interactome servers DRAR-CPI and DDI-CPI, and verified by AutoDock Vina. The results showed that neprilysin (also known as CD10), a common acute lymphoblastic leukaemia antigen, was the top diseaserelated target of arteannuin. The chemical-protein interactome and docking results agreed with those of PharmMapper, further implicating neprilysin as a potential target. Although experimental verification is required, this study provides guidance for future pharmacological investigations into novel clinical applications for arteannuin.Uniterms: Arteannuin/chemical-protein interactome. Computational drug repositioning. Neprilysin/ identification. Reverse docking.

show abstract

Neprilysin and Amyloid Beta Peptide Degradation

Cited by 108 publications

References 73 publications

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric Aβ

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Identification of neprilysin as a potential target of arteannuin using computational drug repositioning

Contact Info

Product

Resources

About