An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss.

Mutations in Amyloid-ß Precursor Protein (APP) and BRI2/ITM2b genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPß and ß-CTF. ß-CTF is cleaved by gamma-secretase to produce Aß. A knock-in mouse model of FDD, ca...

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Autores principales: Franco Lombino, Fabrizio Biundo, Robert Tamayev, Ottavio Arancio, Luciano D'Adamio
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Publicado: Public Library of Science (PLoS) 2013
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Acceso en línea:https://doaj.org/article/b963b79505004cc4be19909306a1c4c0
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spelling oai:doaj.org-article:b963b79505004cc4be19909306a1c4c02021-11-18T07:56:20ZAn intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss.1932-620310.1371/journal.pone.0057120https://doaj.org/article/b963b79505004cc4be19909306a1c4c02013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23451158/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Mutations in Amyloid-ß Precursor Protein (APP) and BRI2/ITM2b genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPß and ß-CTF. ß-CTF is cleaved by gamma-secretase to produce Aß. A knock-in mouse model of FDD, called FDDKI, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPß/ß-CTF but not Aß. We have investigated further the pathogenic function of ß-CTF focusing on Thr(668) of ß-CTF because phosphorylation of Thr(668) is increased in AD cases. We created a knock-in mouse bearing a Thr(668)Ala mutation (APP(TA) mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDDKI mice. These data are consistent with a role for the carboxyl-terminal APP domain in the pathogenesis of dementia and suggest that averting the noxious role of Thr(668) is a viable therapeutic strategy for human dementias.Franco LombinoFabrizio BiundoRobert TamayevOttavio ArancioLuciano D'AdamioLuciano D'AdamioPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 2, p e57120 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Franco Lombino
Fabrizio Biundo
Robert Tamayev
Ottavio Arancio
Luciano D'Adamio
Luciano D'Adamio
An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss.
description Mutations in Amyloid-ß Precursor Protein (APP) and BRI2/ITM2b genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPß and ß-CTF. ß-CTF is cleaved by gamma-secretase to produce Aß. A knock-in mouse model of FDD, called FDDKI, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPß/ß-CTF but not Aß. We have investigated further the pathogenic function of ß-CTF focusing on Thr(668) of ß-CTF because phosphorylation of Thr(668) is increased in AD cases. We created a knock-in mouse bearing a Thr(668)Ala mutation (APP(TA) mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDDKI mice. These data are consistent with a role for the carboxyl-terminal APP domain in the pathogenesis of dementia and suggest that averting the noxious role of Thr(668) is a viable therapeutic strategy for human dementias.
format article
author Franco Lombino
Fabrizio Biundo
Robert Tamayev
Ottavio Arancio
Luciano D'Adamio
Luciano D'Adamio
author_facet Franco Lombino
Fabrizio Biundo
Robert Tamayev
Ottavio Arancio
Luciano D'Adamio
Luciano D'Adamio
author_sort Franco Lombino
title An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss.
title_short An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss.
title_full An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss.
title_fullStr An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss.
title_full_unstemmed An intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss.
title_sort intracellular threonine of amyloid-β precursor protein mediates synaptic plasticity deficits and memory loss.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/b963b79505004cc4be19909306a1c4c0
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