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Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer's Disease
Although a wide variety of genetic and nongenetic Alzheimer's disease (AD) risk factors have been identified, their role in onset and/or progression of neuronal degeneration remains elusive. Systematic analysis of AD risk factors revealed that perturbations of intraneuronal signalling pathways...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi Publishing Corporation
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160617/ https://www.ncbi.nlm.nih.gov/pubmed/25243118 http://dx.doi.org/10.1155/2014/167024 |
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author | Van Dooren, Tom Princen, Katrien De Witte, Koen Griffioen, Gerard |
author_facet | Van Dooren, Tom Princen, Katrien De Witte, Koen Griffioen, Gerard |
author_sort | Van Dooren, Tom |
collection | PubMed |
description | Although a wide variety of genetic and nongenetic Alzheimer's disease (AD) risk factors have been identified, their role in onset and/or progression of neuronal degeneration remains elusive. Systematic analysis of AD risk factors revealed that perturbations of intraneuronal signalling pathways comprise a common mechanistic denominator in both familial and sporadic AD and that such alterations lead to increases in Aβ oligomers (Aβo) formation and phosphorylation of TAU. Conversely, Aβo and TAU impact intracellular signalling directly. This feature entails binding of Aβo to membrane receptors, whereas TAU functionally interacts with downstream transducers. Accordingly, we postulate a positive feedback mechanism in which AD risk factors or genes trigger perturbations of intraneuronal signalling leading to enhanced Aβo formation and TAU phosphorylation which in turn further derange signalling. Ultimately intraneuronal signalling becomes deregulated to the extent that neuronal function and survival cannot be sustained, whereas the resulting elevated levels of amyloidogenic Aβo and phosphorylated TAU species self-polymerizes into the AD plaques and tangles, respectively. |
format | Online Article Text |
id | pubmed-4160617 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-41606172014-09-21 Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer's Disease Van Dooren, Tom Princen, Katrien De Witte, Koen Griffioen, Gerard Biomed Res Int Review Article Although a wide variety of genetic and nongenetic Alzheimer's disease (AD) risk factors have been identified, their role in onset and/or progression of neuronal degeneration remains elusive. Systematic analysis of AD risk factors revealed that perturbations of intraneuronal signalling pathways comprise a common mechanistic denominator in both familial and sporadic AD and that such alterations lead to increases in Aβ oligomers (Aβo) formation and phosphorylation of TAU. Conversely, Aβo and TAU impact intracellular signalling directly. This feature entails binding of Aβo to membrane receptors, whereas TAU functionally interacts with downstream transducers. Accordingly, we postulate a positive feedback mechanism in which AD risk factors or genes trigger perturbations of intraneuronal signalling leading to enhanced Aβo formation and TAU phosphorylation which in turn further derange signalling. Ultimately intraneuronal signalling becomes deregulated to the extent that neuronal function and survival cannot be sustained, whereas the resulting elevated levels of amyloidogenic Aβo and phosphorylated TAU species self-polymerizes into the AD plaques and tangles, respectively. Hindawi Publishing Corporation 2014 2014-08-27 /pmc/articles/PMC4160617/ /pubmed/25243118 http://dx.doi.org/10.1155/2014/167024 Text en Copyright © 2014 Tom Van Dooren et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Review Article Van Dooren, Tom Princen, Katrien De Witte, Koen Griffioen, Gerard Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer's Disease |
title | Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer's Disease |
title_full | Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer's Disease |
title_fullStr | Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer's Disease |
title_full_unstemmed | Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer's Disease |
title_short | Derailed Intraneuronal Signalling Drives Pathogenesis in Sporadic and Familial Alzheimer's Disease |
title_sort | derailed intraneuronal signalling drives pathogenesis in sporadic and familial alzheimer's disease |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160617/ https://www.ncbi.nlm.nih.gov/pubmed/25243118 http://dx.doi.org/10.1155/2014/167024 |
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