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Neurochemical Research

, Volume 41, Issue 3, pp 620–630 | Cite as

New Insights into Epigenetic and Pharmacological Regulation of Amyloid-Degrading Enzymes

  • Natalia N. Nalivaeva
  • Nikolai D. Belyaev
  • Anthony J. Turner
Original Paper

Abstract

Currently, deficit of amyloid β-peptide (Aβ) clearance from the brain is considered as one of the possible causes of amyloid accumulation and neuronal death in the sporadic form of Alzheimer’s disease (AD). Aβ clearance can involve either specific proteases present in the brain or Aβ-binding/transport proteins. Among amyloid-degrading enzymes the most intensively studied are neprilysin (NEP) and insulin-degrading enzyme (IDE). Since ageing and development of brain pathologies is often accompanied by a deficit in the levels of expression and activity of these enzymes in the brain, there is an urgent need to understand the mechanisms involved in their regulation. We have recently reported that NEP and also an Aβ-transport protein, transthyretin are epigenetically co-regulated by the APP intracellular domain (AICD) and this regulation depends on the cell type and APP695 isoform expression in a process that can be regulated by the tyrosine kinase inhibitor, Gleevec. We have now extended our work and shown that, unlike NEP, another amyloid-degrading enzyme, IDE, is not related to over-expression of APP695 in neuroblastoma SH-SY5Y cells but is up-regulated by APP751 and APP770 isoforms independently of AICD but correlating with reduced HDAC1 binding to its promoter. Studying the effect of the nuclear retinoid X receptor agonist, bexarotene, on NEP and IDE expression, we have found that both enzymes can be up-regulated by this compound but this mechanism is not APP-isoform specific and does not involve AICD but, on the contrary, affects HDAC1 occupancy on the NEP gene promoter. These new insights into the mechanisms of NEP and IDE regulation suggest possible pharmacological targets in developing AD therapies.

Keywords

Amyloid peptide APP AICD Bexarotene Histone deacetylases Insulin-degrading enzyme Neprilysin 

Abbreviations

Amyloid β-peptide

AD

Alzheimer’s disease

AICD

APP intracellular domain

APP

Amyloid precursor protein

BX

Bexarotene

ECE

Endothelin-converting enzyme

IDE

Insulin-degrading enzyme

HDAC

Histone deacetylase

NEP

Neprilysin

PKC

Protein kinase C

TTR

Transthyretin

Notes

Acknowledgments

Supported by U.K. Medical Research Council, Alzheimer’s Research UK (CK), FP7-PEOPLE-2010-IEF (EB), RFBR 13-04-00388, Programme of Russian Academy of Science “Fundamental Sciences to Medicine”.

Compliance with Ethical Standards

Conflict of interest

Authors declare no conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Natalia N. Nalivaeva
    • 1
    • 2
  • Nikolai D. Belyaev
    • 1
  • Anthony J. Turner
    • 1
  1. 1.School of Molecular and Cellular Biology, Faculty of Biological SciencesUniversity of LeedsLeedsUK
  2. 2.I.M.Sechenov Institute of Evolutionary Physiology and BiochemistryPetersburgRussia

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