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Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy

Defective autophagy contributes to Alzheimer disease (AD) pathogenesis although evidence is conflicting on whether multiple stages are impaired. Here, for the first time, we have comprehensively evaluated the entire autophagic process specifically in CA1 pyramidal neurons of hippocampus from early a...

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Autores principales: Bordi, Matteo, Berg, Martin J., Mohan, Panaiyur S., Peterhoff, Corrinne M., Alldred, Melissa J., Che, Shaoli, Ginsberg, Stephen D., Nixon, Ralph A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173282/
https://www.ncbi.nlm.nih.gov/pubmed/27813694
http://dx.doi.org/10.1080/15548627.2016.1239003
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author Bordi, Matteo
Berg, Martin J.
Mohan, Panaiyur S.
Peterhoff, Corrinne M.
Alldred, Melissa J.
Che, Shaoli
Ginsberg, Stephen D.
Nixon, Ralph A.
author_facet Bordi, Matteo
Berg, Martin J.
Mohan, Panaiyur S.
Peterhoff, Corrinne M.
Alldred, Melissa J.
Che, Shaoli
Ginsberg, Stephen D.
Nixon, Ralph A.
author_sort Bordi, Matteo
collection PubMed
description Defective autophagy contributes to Alzheimer disease (AD) pathogenesis although evidence is conflicting on whether multiple stages are impaired. Here, for the first time, we have comprehensively evaluated the entire autophagic process specifically in CA1 pyramidal neurons of hippocampus from early and late-stage AD subjects and nondemented controls. CA1 neurons aspirated by laser capture microdissection were analyzed using a custom-designed microarray comprising 578 neuropathology- and neuroscience-associated genes. Striking upregulation of autophagy-related genes, exceeding that of other gene ontology groups, reflected increases in autophagosome formation and lysosomal biogenesis beginning at early AD stages. Upregulated autophagosome formation was further indicated by elevated gene and protein expression levels for autophagosome components and increased LC3-positive puncta. Increased lysosomal biogenesis was evidenced by activation of MiTF/TFE family transcriptional regulators, particularly TFE3 (transcription factor binding to IGHM enhancer 3) and by elevated expression of their target genes and encoded proteins. Notably, TFEB (transcription factor EB) activation was associated more strongly with glia than neurons. These findings establish that autophagic sequestration is both competent and upregulated in AD. Autophagosome-lysosome fusion is not evidently altered. Despite this early disease response, however, autophagy flux is progressively impeded due to deficient substrate clearance, as reflected by autolysosomal accumulation of LC3-II and SQSTM1/p62 and expansion of autolysosomal size and total area. We propose that sustained induction of autophagy in the face of progressively declining lysosomal clearance of substrates explains the uncommonly robust autophagic pathology and neuritic dystrophy implicated in AD pathogenesis.
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spelling pubmed-51732822016-12-22 Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy Bordi, Matteo Berg, Martin J. Mohan, Panaiyur S. Peterhoff, Corrinne M. Alldred, Melissa J. Che, Shaoli Ginsberg, Stephen D. Nixon, Ralph A. Autophagy Basic Research Paper Defective autophagy contributes to Alzheimer disease (AD) pathogenesis although evidence is conflicting on whether multiple stages are impaired. Here, for the first time, we have comprehensively evaluated the entire autophagic process specifically in CA1 pyramidal neurons of hippocampus from early and late-stage AD subjects and nondemented controls. CA1 neurons aspirated by laser capture microdissection were analyzed using a custom-designed microarray comprising 578 neuropathology- and neuroscience-associated genes. Striking upregulation of autophagy-related genes, exceeding that of other gene ontology groups, reflected increases in autophagosome formation and lysosomal biogenesis beginning at early AD stages. Upregulated autophagosome formation was further indicated by elevated gene and protein expression levels for autophagosome components and increased LC3-positive puncta. Increased lysosomal biogenesis was evidenced by activation of MiTF/TFE family transcriptional regulators, particularly TFE3 (transcription factor binding to IGHM enhancer 3) and by elevated expression of their target genes and encoded proteins. Notably, TFEB (transcription factor EB) activation was associated more strongly with glia than neurons. These findings establish that autophagic sequestration is both competent and upregulated in AD. Autophagosome-lysosome fusion is not evidently altered. Despite this early disease response, however, autophagy flux is progressively impeded due to deficient substrate clearance, as reflected by autolysosomal accumulation of LC3-II and SQSTM1/p62 and expansion of autolysosomal size and total area. We propose that sustained induction of autophagy in the face of progressively declining lysosomal clearance of substrates explains the uncommonly robust autophagic pathology and neuritic dystrophy implicated in AD pathogenesis. Taylor & Francis 2016-11-04 /pmc/articles/PMC5173282/ /pubmed/27813694 http://dx.doi.org/10.1080/15548627.2016.1239003 Text en © 2016 The Author(s). Published with license by Taylor & Francis http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.
spellingShingle Basic Research Paper
Bordi, Matteo
Berg, Martin J.
Mohan, Panaiyur S.
Peterhoff, Corrinne M.
Alldred, Melissa J.
Che, Shaoli
Ginsberg, Stephen D.
Nixon, Ralph A.
Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy
title Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy
title_full Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy
title_fullStr Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy
title_full_unstemmed Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy
title_short Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy
title_sort autophagy flux in ca1 neurons of alzheimer hippocampus: increased induction overburdens failing lysosomes to propel neuritic dystrophy
topic Basic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5173282/
https://www.ncbi.nlm.nih.gov/pubmed/27813694
http://dx.doi.org/10.1080/15548627.2016.1239003
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