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Title: Alzheimer's Aβ 1‐40 peptide degradation by thermolysin: evidence of inhibition by a C‐terminal Aβ product

Journal Article · · FEBS Letters
 [1];  [1]
  1. i3S – Instituto de Investigação e Inovação em Saúde Porto Portugal, IBMC – Instituto de Biologia Molecular e Celular Universidade do Porto Portugal, ICBAS – Instituto de Ciências Biomédicas Abel Salazar Porto Portugal

The interaction of the amyloid‐β peptide (Aβ) with thermolysin ( TLN ) was investigated by X‐ray crystallography. Structural models of the complexes of TLN with several Aβ fragments show that, despite the numerous possible cleavage sites of the Aβ sequence, the C‐terminal product of Ala30‐Ile31 cleavage does not dissociate, thus inhibiting the enzyme. The high similarity between the TLN structural motif and neprilysin ( NEP ), the most extensively studied peptidase associated with Aβ clearance, suggests that NEP should be more efficient against Aβ polymorphs where Ala30‐Ile31 is inaccessible, which is in agreement with studies in living mice that point to the limited role of NEP in degrading soluble Aβ and its higher ability to degrade insoluble and/or oligomeric Aβ forms, producing only the Aβ 10–37 intermediate.

Sponsoring Organization:
USDOE
OSTI ID:
1483142
Journal Information:
FEBS Letters, Journal Name: FEBS Letters Journal Issue: 1 Vol. 593; ISSN 0014-5793
Publisher:
Wiley Blackwell (John Wiley & Sons)Copyright Statement
Country of Publication:
Netherlands
Language:
English

References (54)

Clearing the Brain's Amyloid Cobwebs journal October 2001
Free R value: a novel statistical quantity for assessing the accuracy of crystal structures journal January 1992
Degradation of the Amyloid β-Protein by the Novel Mitochondrial Peptidasome, PreP journal July 2006
The amyloid hypothesis of Alzheimer's disease at 25 years journal March 2016
Structure of human neutral endopeptidase (neprilysin) complexed with phosphoramidon 1 1Edited by R. Huber journal February 2000
Overexpression of Neprilysin Reduces Alzheimer Amyloid-β42 (Aβ42)-induced Neuron Loss and Intraneuronal Aβ42 Deposits but Causes a Reduction in cAMP-responsive Element-binding Protein-mediated Transcription, Age-dependent Axon Pathology, and Premature Death in Drosophila journal May 2008
Crystal Structure of the Amyloid-  p3 Fragment Provides a Model for Oligomer Formation in Alzheimer's Disease journal January 2011
Features and development of Coot journal March 2010
Neprilysin Degrades Both Amyloid β Peptides 1–40 and 1–42 Most Rapidly and Efficiently among Thiorphan- and Phosphoramidon-sensitive Endopeptidases journal March 2001
Clearance of Extracellular and Cell-Associated Amyloid   Peptide through Viral Expression of Neprilysin in Primary Neurons journal December 2001
A New Structural Model of Aβ 40 Fibrils journal October 2011
Physiological roles for amyloid β peptides: Physiological roles for amyloid β peptides journal August 2006
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Gantenerumab: A Novel Human Anti-Aβ Antibody Demonstrates Sustained Cerebral Amyloid-β Binding and Elicits Cell-Mediated Removal of Human Amyloid-β journal January 2012
Molecular Basis of Substrate Recognition and Degradation by Human Presequence Protease journal July 2014
Thermolysin in the absence of substrate has an open conformation journal May 2002
Neprilysin-sensitive Synapse-associated Amyloid-β Peptide Oligomers Impair Neuronal Plasticity and Cognitive Function journal April 2006
Peripherally expressed neprilysin reduces brain amyloid burden: A novel approach for treating Alzheimer's disease journal May 2009
Plasminogen and plasmin in Alzheimer's disease journal October 2010
Phaser crystallographic software journal July 2007
Bapineuzumab captures the N-terminus of the Alzheimer's disease amyloid-beta peptide in a helical conformation journal February 2013
Structure of amyloid beta fragments in aqueous environments journal January 2006
A coiled conformation of amyloid-β recognized by antibody C706 journal August 2017
Identification of the major Aβ1–42-degrading catabolic pathway in brain parenchyma: Suppression leads to biochemical and pathological deposition journal February 2000
Solvent content of protein crystals journal April 1968
Structural Basis of C-terminal β-Amyloid Peptide Binding by the Antibody Ponezumab for the Treatment of Alzheimer's Disease journal August 2012
Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease journal August 2010
Structural studies of the tethered N-terminus of the Alzheimer's disease amyloid-β peptide: Aβ N-Terminal Structural Studies journal July 2013
Structural Correlates of Antibodies Associated with Acute Reversal of Amyloid β-related Behavioral Deficits in a Mouse Model of Alzheimer Disease journal November 2009
Antiamyloidogenic and Neuroprotective Functions of Cathepsin B: Implications for Alzheimer's Disease journal September 2006
Neutral endopeptidase can hydrolyze β-amyloid(1–40) but shows no effect on β-amyloid precursor protein metabolism journal January 1995
Molecular basis for mid-region amyloid-β capture by leading Alzheimer's disease immunotherapies journal April 2015
Matrix Metalloproteinase-9 (MMP-9) Is Synthesized in Neurons of the Human Hippocampus and Is Capable of Degrading the Amyloid-β Peptide (1–40) journal December 1996
Amyloid-β–Anti-Amyloid-β Complex Structure Reveals an Extended Conformation in the Immunodominant B-Cell Epitope journal March 2008
Effect of Glu-143 and His-231 substitutions on the catalytic activity and secretion of Bacillus subtilis neutral protease journal January 1989
Structure of Crenezumab Complex with Aβ Shows Loss of β-Hairpin journal December 2016
Amyloid beta: structure, biology and structure-based therapeutic development journal July 2017
Kidney neutral endopeptidase and the hydrolysis of enkephalin by synaptic membranes show similar sensitivity to inhibitors journal May 1982
Elucidating the Origin of Long Residence Time Binding for Inhibitors of the Metalloprotease Thermolysin journal December 2016
Kinetics of Amyloid β-Protein Degradation Determined by Novel Fluorescence- and Fluorescence Polarization-based Assays journal July 2003
Structural analysis of zinc substitutions in the active site of thermolysin journal October 1995
Functional activity of the novel Alzheimer's amyloid β-peptide interacting domain (AβID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis journal November 2011
Interprotofilament interactions between Alzheimer's A 1-42 peptides in amyloid fibrils revealed by cryoEM journal March 2009
Does Aβ 42 Have a Function Related to Blood Homeostasis? journal December 2006
Automatic processing of rotation diffraction data from crystals of initially unknown symmetry and cell constants journal December 1993
Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism journal October 2006
The Plasmin System Is Induced by and Degrades Amyloid-β Aggregates journal June 2000
Self-Propagating, Molecular-Level Polymorphism in Alzheimer's  -Amyloid Fibrils journal January 2005
Alzheimer's disease drug development pipeline: 2017 journal September 2017
Molecular basis for passive immunotherapy of Alzheimer's disease journal September 2007
Molecular basis for amyloid-  polymorphism journal September 2011
Neprilysin Gene Transfer Reduces Human Amyloid Pathology in Transgenic Mice journal March 2003
Kinetic and structural characterization of amyloid-β peptide hydrolysis by human angiotensin-1-converting enzyme journal February 2016
Matrix Metalloproteinase-9 Degrades Amyloid-β Fibrils in Vitro and Compact Plaques in Situ journal June 2006