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Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis

Alzheimer’s disease (AD) belongs to a category of adult neurodegenerative conditions which are associated with intracellular and extracellular accumulation of neurotoxic protein aggregates. Understanding how these aggregates are formed, secreted and propagated by neurons has been the subject of inte...

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Autores principales: Annunziata, Ida, Patterson, Annette, Helton, Danielle, Hu, Huimin, Moshiach, Simon, Gomero, Elida, Nixon, Ralph, d’Azzo, Alessandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015463/
https://www.ncbi.nlm.nih.gov/pubmed/24225533
http://dx.doi.org/10.1038/ncomms3734
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author Annunziata, Ida
Patterson, Annette
Helton, Danielle
Hu, Huimin
Moshiach, Simon
Gomero, Elida
Nixon, Ralph
d’Azzo, Alessandra
author_facet Annunziata, Ida
Patterson, Annette
Helton, Danielle
Hu, Huimin
Moshiach, Simon
Gomero, Elida
Nixon, Ralph
d’Azzo, Alessandra
author_sort Annunziata, Ida
collection PubMed
description Alzheimer’s disease (AD) belongs to a category of adult neurodegenerative conditions which are associated with intracellular and extracellular accumulation of neurotoxic protein aggregates. Understanding how these aggregates are formed, secreted and propagated by neurons has been the subject of intensive research, but so far no preventive or curative therapy for AD is available and clinical trials have been largely unsuccessful. Here we show that deficiency of the lysosomal sialidase NEU1 leads to the spontaneous occurrence of an AD-like amyloidogenic process in mice. This involves two consecutive events linked to NEU1 loss-of-function – accumulation and amyloidogenic processing of an oversialylated amyloid precursor protein in lysosomes, and extracellular release of Aβ-peptides by excessive lysosomal exocytosis. Furthermore, cerebral injection of NEU1 in an established AD mouse model substantially reduces β-amyloid plaques. Our findings identify an additional pathway for the secretion of Aβ and define NEU1 as a potential therapeutic molecule for AD.
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spelling pubmed-40154632014-05-14 Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis Annunziata, Ida Patterson, Annette Helton, Danielle Hu, Huimin Moshiach, Simon Gomero, Elida Nixon, Ralph d’Azzo, Alessandra Nat Commun Article Alzheimer’s disease (AD) belongs to a category of adult neurodegenerative conditions which are associated with intracellular and extracellular accumulation of neurotoxic protein aggregates. Understanding how these aggregates are formed, secreted and propagated by neurons has been the subject of intensive research, but so far no preventive or curative therapy for AD is available and clinical trials have been largely unsuccessful. Here we show that deficiency of the lysosomal sialidase NEU1 leads to the spontaneous occurrence of an AD-like amyloidogenic process in mice. This involves two consecutive events linked to NEU1 loss-of-function – accumulation and amyloidogenic processing of an oversialylated amyloid precursor protein in lysosomes, and extracellular release of Aβ-peptides by excessive lysosomal exocytosis. Furthermore, cerebral injection of NEU1 in an established AD mouse model substantially reduces β-amyloid plaques. Our findings identify an additional pathway for the secretion of Aβ and define NEU1 as a potential therapeutic molecule for AD. 2013 /pmc/articles/PMC4015463/ /pubmed/24225533 http://dx.doi.org/10.1038/ncomms3734 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Annunziata, Ida
Patterson, Annette
Helton, Danielle
Hu, Huimin
Moshiach, Simon
Gomero, Elida
Nixon, Ralph
d’Azzo, Alessandra
Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
title Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
title_full Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
title_fullStr Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
title_full_unstemmed Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
title_short Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
title_sort lysosomal neu1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015463/
https://www.ncbi.nlm.nih.gov/pubmed/24225533
http://dx.doi.org/10.1038/ncomms3734
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