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APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells

Amyloid precursor protein (APP) is processed along both the nonamyloidogenic pathway preventing amyloid beta peptide (Aβ) production and the amyloidogenic pathway, generating Aβ, whose accumulation characterizes Alzheimer’s disease. Items of evidence report that the intracellular trafficking plays a...

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Autores principales: Bhattacharya, Antaripa, Limone, Adriana, Napolitano, Filomena, Cerchia, Carmen, Parisi, Silvia, Minopoli, Giuseppina, Montuori, Nunzia, Lavecchia, Antonio, Sarnataro, Daniela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084285/
https://www.ncbi.nlm.nih.gov/pubmed/32143270
http://dx.doi.org/10.3390/ijms21051738
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author Bhattacharya, Antaripa
Limone, Adriana
Napolitano, Filomena
Cerchia, Carmen
Parisi, Silvia
Minopoli, Giuseppina
Montuori, Nunzia
Lavecchia, Antonio
Sarnataro, Daniela
author_facet Bhattacharya, Antaripa
Limone, Adriana
Napolitano, Filomena
Cerchia, Carmen
Parisi, Silvia
Minopoli, Giuseppina
Montuori, Nunzia
Lavecchia, Antonio
Sarnataro, Daniela
author_sort Bhattacharya, Antaripa
collection PubMed
description Amyloid precursor protein (APP) is processed along both the nonamyloidogenic pathway preventing amyloid beta peptide (Aβ) production and the amyloidogenic pathway, generating Aβ, whose accumulation characterizes Alzheimer’s disease. Items of evidence report that the intracellular trafficking plays a key role in the generation of Aβ and that the 37/67 kDa LR (laminin receptor), acting as a receptor for Aβ, may mediate Aβ-pathogenicity. Moreover, findings indicating interaction between the receptor and the key enzymes involved in the amyloidogenic pathway suggest a strong link between 37/67 kDa LR and APP processing. We show herein that the specific 37/67 kDa LR inhibitor, NSC48478, is able to reversibly affect the maturation of APP in a pH-dependent manner, resulting in the partial accumulation of the immature APP isoforms (unglycosylated/acetylated forms) in the endoplasmic reticulum (ER) and in transferrin-positive recycling endosomes, indicating alteration of the APP intracellular trafficking. These effects reveal NSC48478 inhibitor as a novel small molecule to be tested in disease conditions, mediated by the 37/67 kDa LR and accompanied by inactivation of ERK1/2 (extracellular signal-regulated kinases) signalling and activation of Akt (serine/threonine protein kinase) with consequent inhibition of GSK3β.
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spelling pubmed-70842852020-03-24 APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells Bhattacharya, Antaripa Limone, Adriana Napolitano, Filomena Cerchia, Carmen Parisi, Silvia Minopoli, Giuseppina Montuori, Nunzia Lavecchia, Antonio Sarnataro, Daniela Int J Mol Sci Article Amyloid precursor protein (APP) is processed along both the nonamyloidogenic pathway preventing amyloid beta peptide (Aβ) production and the amyloidogenic pathway, generating Aβ, whose accumulation characterizes Alzheimer’s disease. Items of evidence report that the intracellular trafficking plays a key role in the generation of Aβ and that the 37/67 kDa LR (laminin receptor), acting as a receptor for Aβ, may mediate Aβ-pathogenicity. Moreover, findings indicating interaction between the receptor and the key enzymes involved in the amyloidogenic pathway suggest a strong link between 37/67 kDa LR and APP processing. We show herein that the specific 37/67 kDa LR inhibitor, NSC48478, is able to reversibly affect the maturation of APP in a pH-dependent manner, resulting in the partial accumulation of the immature APP isoforms (unglycosylated/acetylated forms) in the endoplasmic reticulum (ER) and in transferrin-positive recycling endosomes, indicating alteration of the APP intracellular trafficking. These effects reveal NSC48478 inhibitor as a novel small molecule to be tested in disease conditions, mediated by the 37/67 kDa LR and accompanied by inactivation of ERK1/2 (extracellular signal-regulated kinases) signalling and activation of Akt (serine/threonine protein kinase) with consequent inhibition of GSK3β. MDPI 2020-03-04 /pmc/articles/PMC7084285/ /pubmed/32143270 http://dx.doi.org/10.3390/ijms21051738 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bhattacharya, Antaripa
Limone, Adriana
Napolitano, Filomena
Cerchia, Carmen
Parisi, Silvia
Minopoli, Giuseppina
Montuori, Nunzia
Lavecchia, Antonio
Sarnataro, Daniela
APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells
title APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells
title_full APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells
title_fullStr APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells
title_full_unstemmed APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells
title_short APP Maturation and Intracellular Localization Are Controlled by a Specific Inhibitor of 37/67 kDa Laminin-1 Receptor in Neuronal Cells
title_sort app maturation and intracellular localization are controlled by a specific inhibitor of 37/67 kda laminin-1 receptor in neuronal cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084285/
https://www.ncbi.nlm.nih.gov/pubmed/32143270
http://dx.doi.org/10.3390/ijms21051738
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