Human neprilysin is capable of degrading amyloid β peptide not only in the monomeric form but also the pathological oligomeric form

doi:10.1016/S0304-3940(03)00898-X

Neuroscience Letters

Volume 350, Issue 2, 23 October 2003, Pages 113-116

https://doi.org/10.1016/S0304-3940(03)00898-X Get rights and content

Abstract

Amyloid β-peptide (Aβ) is widely believed to play a central role in Alzheimer's disease (AD). Coordinate regulation of cerebral Aβ level is important in the pathogenesis of AD since either increased production of Aβ from amyloid precursor protein or decreased degradation causes elevated levels of Aβ, leading to accumulation of cerebral plaque formation or amyloid angiopathy. Here we studied neprilysin, a putative proteolytic enzyme for Aβ, and found that it degraded not only monomeric but also oligomeric forms of Aβ1–40. Moreover, neprilysin was found to be capable of degradation of the oligomeric form of Aβ1–42, a significant Aβ species in early pathogenesis. Neprilysin to decrease cerebral Aβ is suggested to be inevitable factor as a vital therapeutic target.

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Acknowledgements

The present study was supported in part by the Grant-in-Aid for Scientific Research on Priority Areas (c) and Osaka Gus Foundation for HM.

References (23)

K.N. Dahlgren et al.
Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability
J. Biol. Chem.
(2002)
H. Mori et al.
Mass spectrometry of purified amyloid β protein in Alzheimer's disease
J. Biol. Chem.
(1992)
B.P. Roques et al.
Inhibitors of neprilysin: design, pharmacological and clinical applications
Methods Enzymol.
(1995)
K.A. Seta et al.
Overexpression of insulin degrading enzyme: cellular localization and effects on insulin signaling
Biochem. Biophys. Res. Commun.
(1997)
K. Yasojima et al.
Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of β-amyloid peptide
Neurosci. Lett.
(2001)
O. Berezovska et al.
Amyloid precursor protein associates with a nicastrin-dependent docking site on the presenilin l-gamma-secretase complex in cells demonstrated by fluorescence lifetime imaging
J. Neurosci.
(2003)
L. Bertram et al.
Evidence for genetic linkage of Alzheimer's disease to chromosome 10q
Science
(2000)
E.H. Corder et al.
Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
Science
(1993)
W.C. Duckworth et al.
Insulin degradation: progress and potential
Endocr. Rev.
(1998)
R. Ehehalt et al.
Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts
J. Cell Biol.
(2003)

N. Ertekin-Taner et al.

Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees

Science

(2000)

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Effects of DHA (omega-3 fatty acid) and estradiol on amyloid β-peptide regulation in the brain
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In the early stages of sporadic Alzheimer’s disease (SAD), there is a strong correlation between memory impairment and cortical levels of soluble amyloid-β peptide oligomers (Aβ). It has become clear that Aβ disrupt glutamatergic synaptic function, which can in turn lead to the characteristic cognitive deficits of SAD, but the actual pathways are still not well understood. This opinion article describes the pathogenic mechanisms underlying cerebral amyloidosis. These mechanisms are dependent on the amyloid precursor protein and concern the synthesis of Aβ peptides with competition between the non-amyloidogenic pathway and the amyloidogenic pathway (i.e. a competition between the ADAM10 and BACE1 enzymes), on the one hand, and the various processes of Aβ residue clearance, on the other hand. This clearance mobilizes both endopeptidases (NEP, and IDE) and removal transporters across the blood–brain barrier (LRP1, ABCB1, and RAGE). Lipidated ApoE also plays a major role in all processes. The disturbance of these pathways induces an accumulation of Aβ. The description of the mechanisms reveals two key molecules in particular: (i) free estradiol, which has genomic and non-genomic action, and (ii) free DHA as a preferential ligand of PPARα-RXRα and PPARɣ-RXRα heterodimers. DHA and free estradiol are also self-regulating, and act in synergy. When a certain level of chronic DHA and free estradiol deficiency is reached, a permanent imbalance is established in the central nervous system. The consequences of these deficits are revealed in particular by the presence of Aβ peptide deposits, as well as other markers of the etiology of SAD.
Novel developments in non-contrast enhanced MRI of the perivascular clearance system: What are the possibilities for Alzheimer's disease research?
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The cerebral waste clearance system (i.e, glymphatic or intramural periarterial drainage) works through a network of perivascular spaces (PVS). Dysfunction of this system likely contributes to aggregation of Amyloid-β and subsequent toxic plaques in Alzheimer’s disease (AD). A promising, non-invasive technique to study this system is MRI, though applications in dementia are still scarce. This review focusses on recent non-contrast enhanced (non-CE) MRI techniques which determine and visualise physiological aspects of the clearance system at multiple levels, i.e., cerebrospinal fluid flow, PVS-flow and interstitial fluid movement. Furthermore, various MRI studies focussing on aspects of the clearance system which are relevant to AD are discussed, such as studies on ageing, sleep alterations, and cognitive decline. Additionally, the complementary function of non-CE to CE methods is elaborated upon. We conclude that non-CE studies have great potential to determine which parts of the waste clearance system are affected by AD and in which stages of cognitive impairment dysfunction of this system occurs, which could allow future clinical trials to target these specific mechanisms.
Comparative studies for amyloid beta degradation: “Neprilysin vs insulysin”, “monomeric vs aggregate”, and “whole Aβ<inf>40</inf> vs its peptide fragments”
2022, Biochemistry and Biophysics Reports
Amyloid beta (Aβ) proteins are produced from amyloid precursor protein cleaved by β- and γ-secretases, and are the main components of senile plaques pathologically found in Alzheimer's disease (AD) patient brains. Therefore, the relationship between AD and Aβs has been well studied for both therapeutic and diagnostic purposes. Several enzymes have been reported to degrade Aβs in vivo, with neprilysin (NEP) and insulysin (insulin-degrading enzyme, IDE) being the most prominent. In this article, we describe the mass spectrometric characterization of peptide fragments generated using NEP and IDE, and clarify the differences in digestion specificities between these two enzymes for non-aggregated Aβ₄₀, aggregated Aβ₄₀, and Aβ₄₀ peptide fragments, including Aβ₁₆. Our results allowed identification of all the peptide fragments from non-aggregated Aβ₄₀: NEP, 23 peptide fragments consisting of 2–11 amino-acid residues, 17 cleavage sites; IDE, 23 peptide fragments consisting of 6–33 amino-acid residues, 15 cleavage sites. Also, we confirmed that IDE can digest only whole Aβ₄₀, whereas NEP can digest both Aβ₄₀ and partial structures such as Aβ₁₆ and peptide fragments generated by the digestion of Aβ₄₀ by IDE. Furthermore, we confirmed that IDE and NEP are unable to digest aggregated Aβ₄₀.
Hypothesis: Intravenous administration of mesenchymal stem cells is effective in the treatment of Alzheimer's disease
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We propose the intravenous administration of autologous adipose-derived stem cells as a new treatment for Alzheimer's disease. We hypothesize that the stem cells will secrete neprilysin in the brain to break down and remove amyloid deposits in the Alzheimer's brain. We have shown a case of skin amyloid deposition that disappeared after stem cell administration and confirmed that the stem cells administered had neprilysin activity. In addition to neprilysin secretion, other mechanisms of action of stem cells include nerve regeneration, nerve repair, growth factor secretion, anti-inflammatory effects, and angiogenesis. The harvesting of adipose-derived stem cells is minimally invasive, and intravenous administration can be safely repeated. We hope that the efficacy of this new treatment will be verified and that it will bring a ray of hope to patients suffering from this incurable disease.
Neuroinflammation drives APOE genotype-dependent differential expression of neprilysin
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Citation Excerpt :
NEP is a zinc-dependent metallopeptidase previously identified as an important ADE in brain (Iwata et al., 2000; Iwata et al., 2001; Shirotani et al., 2001; El-Amouri et al., 2008). It is believed to serve a protective role against AD because of its broad capacity for degrading monomeric, oligomeric, and fibrillar forms of Aβ (Kanemitsu et al., 2003; Numata and Kaplan, 2010; Zraika et al., 2010), and thus represents a potential therapeutic target in AD. In support of this, NEP-deficient mice exhibit elevated steady-state amyloid levels (Eckman et al., 2006; Iwata et al., 2001), and enzyme overexpression in amyloidogenic mice results in reduced cerebral Aβ deposition and neuroinflammatory markers, as well as reduced disease-associated cognitive deficits (Marr et al., 2003; El-Amouri et al., 2008).
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by the deposition of amyloid-beta (Aβ) plaques and widespread neuroinflammation. While the cause of AD remains unknown, multiple factors likely contribute to the disease, including heart disease, diabetes, previous head injury, as well as a number of genetic determinants. Inheritance of the apolipoprotein (APOE) ε4 allele represents the strongest genetic risk factor for development of AD, driving pathogenesis and increasing overall disease severity. APOE has long been recognized as a key regulator of cholesterol homeostasis, although a greater appreciation now exists for its role in various innate immune system processes. Indeed, APOE modulates inflammatory environments in brain in large part by altering gene expression profiles in glia, important mediators of immunity in the CNS. While the association between APOE and AD was first observed nearly three decades ago, the mechanism by which APOE ε4 influences the etiology and pathophysiology of AD is not well characterized. Overwhelming data supports the hypothesis that APOE ε4 dysregulates central amyloid metabolism by an undetermined molecular mechanism, thus laying the foundation for disease. A host of amyloid-degrading enzymes (ADEs) regulate Aβ accumulation in brain, and therefore represent valuable therapeutic targets. Neprilysin (NEP), a metalloendopeptidase expressed by activated microglia and astrocytes, is a broad-spectrum ADE able to degrade a variety of Aβ species. Here we describe in vivo and in vitro experiments designed to investigate the potential for APOE genotype to differentially regulate glial NEP in brain under neuroinflammatory conditions. Our results provide a novel mechanism by which APOE genotype-dependent differential expression of NEP by glia during neuroinflammation may contribute to AD pathogenesis.
Modelling Alzheimer’s disease in a dish: dissecting amyloid-β metabolism in human neurons
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Neuroscience Letters

Abstract

Section snippets

Acknowledgements

References (23)

Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability

J. Biol. Chem.

Mass spectrometry of purified amyloid β protein in Alzheimer's disease

J. Biol. Chem.

Inhibitors of neprilysin: design, pharmacological and clinical applications

Methods Enzymol.

Overexpression of insulin degrading enzyme: cellular localization and effects on insulin signaling

Biochem. Biophys. Res. Commun.

Reduced neprilysin in high plaque areas of Alzheimer brain: a possible relationship to deficient degradation of β-amyloid peptide

Neurosci. Lett.

Amyloid precursor protein associates with a nicastrin-dependent docking site on the presenilin l-gamma-secretase complex in cells demonstrated by fluorescence lifetime imaging

J. Neurosci.

Evidence for genetic linkage of Alzheimer's disease to chromosome 10q

Science

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

Science

Insulin degradation: progress and potential

Endocr. Rev.

Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts

J. Cell Biol.

Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees

Science

Cited by (199)

Effects of DHA (omega-3 fatty acid) and estradiol on amyloid β-peptide regulation in the brain

Novel developments in non-contrast enhanced MRI of the perivascular clearance system: What are the possibilities for Alzheimer's disease research?

Comparative studies for amyloid beta degradation: “Neprilysin vs insulysin”, “monomeric vs aggregate”, and “whole Aβ<inf>40</inf> vs its peptide fragments”

Hypothesis: Intravenous administration of mesenchymal stem cells is effective in the treatment of Alzheimer's disease

Neuroinflammation drives APOE genotype-dependent differential expression of neprilysin

Modelling Alzheimer’s disease in a dish: dissecting amyloid-β metabolism in human neurons