Improved learning and memory in aged mice deficient in amyloid beta-degrading neutral endopeptidase.

<h4>Background</h4>Neutral endopeptidase, also known as neprilysin and abbreviated NEP, is considered to be one of the key enzymes in initial human amyloid-beta (Abeta) degradation. The aim of our study was to explore the impact of NEP deficiency on the initial development of dementia-li...

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Autores principales: Thomas Walther, Doris Albrecht, Matthias Becker, Manja Schubert, Elena Kouznetsova, Burkard Wiesner, Björn Maul, Reinhard Schliebs, Gisela Grecksch, Jens Furkert, Anja Sterner-Kock, Heinz-Peter Schultheiss, Axel Becker, Wolf-Eberhard Siems
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spelling oai:doaj.org-article:dd9c715bc1034a5fa52e7b851539303a2021-11-25T06:17:07ZImproved learning and memory in aged mice deficient in amyloid beta-degrading neutral endopeptidase.1932-620310.1371/journal.pone.0004590https://doaj.org/article/dd9c715bc1034a5fa52e7b851539303a2009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19240795/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Neutral endopeptidase, also known as neprilysin and abbreviated NEP, is considered to be one of the key enzymes in initial human amyloid-beta (Abeta) degradation. The aim of our study was to explore the impact of NEP deficiency on the initial development of dementia-like symptoms in mice.<h4>Methodology/principal findings</h4>We found that while endogenous Abeta concentrations were elevated in the brains of NEP-knockout mice at all investigated age groups, immunohistochemical analysis using monoclonal antibodies did not detect any Abeta deposits even in old NEP knockout mice. Surprisingly, tests of learning and memory revealed that the ability to learn was not reduced in old NEP-deficient mice but instead had significantly improved, and sustained learning and memory in the aged mice was congruent with improved long-term potentiation (LTP) in brain slices of the hippocampus and lateral amygdala. Our data suggests a beneficial effect of pharmacological inhibition of cerebral NEP on learning and memory in mice due to the accumulation of peptides other than Abeta degradable by NEP. By conducting degradation studies and peptide measurements in the brain of both genotypes, we identified two neuropeptide candidates, glucagon-like peptide 1 and galanin, as first potential candidates to be involved in the improved learning in aged NEP-deficient mice.<h4>Conclusions/significance</h4>Thus, the existence of peptides targeted by NEP that improve learning and memory in older individuals may represent a promising avenue for the treatment of neurodegenerative diseases.Thomas WaltherDoris AlbrechtMatthias BeckerManja SchubertElena KouznetsovaBurkard WiesnerBjörn MaulReinhard SchliebsGisela GreckschJens FurkertAnja Sterner-KockHeinz-Peter SchultheissAxel BeckerWolf-Eberhard SiemsPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 2, p e4590 (2009)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Thomas Walther
Doris Albrecht
Matthias Becker
Manja Schubert
Elena Kouznetsova
Burkard Wiesner
Björn Maul
Reinhard Schliebs
Gisela Grecksch
Jens Furkert
Anja Sterner-Kock
Heinz-Peter Schultheiss
Axel Becker
Wolf-Eberhard Siems
Improved learning and memory in aged mice deficient in amyloid beta-degrading neutral endopeptidase.
description <h4>Background</h4>Neutral endopeptidase, also known as neprilysin and abbreviated NEP, is considered to be one of the key enzymes in initial human amyloid-beta (Abeta) degradation. The aim of our study was to explore the impact of NEP deficiency on the initial development of dementia-like symptoms in mice.<h4>Methodology/principal findings</h4>We found that while endogenous Abeta concentrations were elevated in the brains of NEP-knockout mice at all investigated age groups, immunohistochemical analysis using monoclonal antibodies did not detect any Abeta deposits even in old NEP knockout mice. Surprisingly, tests of learning and memory revealed that the ability to learn was not reduced in old NEP-deficient mice but instead had significantly improved, and sustained learning and memory in the aged mice was congruent with improved long-term potentiation (LTP) in brain slices of the hippocampus and lateral amygdala. Our data suggests a beneficial effect of pharmacological inhibition of cerebral NEP on learning and memory in mice due to the accumulation of peptides other than Abeta degradable by NEP. By conducting degradation studies and peptide measurements in the brain of both genotypes, we identified two neuropeptide candidates, glucagon-like peptide 1 and galanin, as first potential candidates to be involved in the improved learning in aged NEP-deficient mice.<h4>Conclusions/significance</h4>Thus, the existence of peptides targeted by NEP that improve learning and memory in older individuals may represent a promising avenue for the treatment of neurodegenerative diseases.
format article
author Thomas Walther
Doris Albrecht
Matthias Becker
Manja Schubert
Elena Kouznetsova
Burkard Wiesner
Björn Maul
Reinhard Schliebs
Gisela Grecksch
Jens Furkert
Anja Sterner-Kock
Heinz-Peter Schultheiss
Axel Becker
Wolf-Eberhard Siems
author_facet Thomas Walther
Doris Albrecht
Matthias Becker
Manja Schubert
Elena Kouznetsova
Burkard Wiesner
Björn Maul
Reinhard Schliebs
Gisela Grecksch
Jens Furkert
Anja Sterner-Kock
Heinz-Peter Schultheiss
Axel Becker
Wolf-Eberhard Siems
author_sort Thomas Walther
title Improved learning and memory in aged mice deficient in amyloid beta-degrading neutral endopeptidase.
title_short Improved learning and memory in aged mice deficient in amyloid beta-degrading neutral endopeptidase.
title_full Improved learning and memory in aged mice deficient in amyloid beta-degrading neutral endopeptidase.
title_fullStr Improved learning and memory in aged mice deficient in amyloid beta-degrading neutral endopeptidase.
title_full_unstemmed Improved learning and memory in aged mice deficient in amyloid beta-degrading neutral endopeptidase.
title_sort improved learning and memory in aged mice deficient in amyloid beta-degrading neutral endopeptidase.
publisher Public Library of Science (PLoS)
publishDate 2009
url https://doaj.org/article/dd9c715bc1034a5fa52e7b851539303a
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