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dc.contributor.author
Mohamed, Amany
dc.contributor.author
Saavedra, Maria Lucila
dc.contributor.author
Di Pardo, Alba
dc.contributor.author
Sipione, Simonetta
dc.contributor.author
Posse de Chaves, Elena
dc.date.available
2017-09-26T17:45:10Z
dc.date.issued
2012-05-09
dc.identifier.citation
Mohamed, Amany; Saavedra, Maria Lucila; Di Pardo, Alba; Sipione, Simonetta; Posse de Chaves, Elena; β-amyloid inhibits protein prenylation and induces cholesterol sequestration by impairing SREBP-2 cleavage; Society for Neuroscience; Journal of Neuroscience; 32; 19; 9-5-2012; 6490-6500
dc.identifier.issn
0270-6474
dc.identifier.uri
http://hdl.handle.net/11336/25133
dc.description.abstract
Accumulation of β-amyloid (Aβ) inside brain neurons is an early and crucial event in Alzheimer's disease (AD). Studies in brains of AD patients and mice models of AD suggested that cholesterol homeostasis is altered in neurons that accumulate Aβ. Here we directly investigated the role of intracellular oligomeric Aβ(42) (oAβ(42)) in neuronal cholesterol homeostasis. We report that oAβ(42) induces cholesterol sequestration without increasing cellular cholesterol mass. Several features of AD, such as endosomal abnormalities, brain accumulation of Aβ and neurofibrillary tangles, and influence of apolipoprotein E genotype, are also present in Niemann-Pick type C, a disease characterized by impairment of intracellular cholesterol trafficking. These common features and data presented here suggest that a pathological mechanism involving abnormal cholesterol trafficking could take place in AD. Cholesterol sequestration in Aβ-treated neurons results from impairment of intracellular cholesterol trafficking secondary to inhibition of protein prenylation. oAβ(42) reduces sterol regulatory element-binding protein-2 (SREBP-2) cleavage, causing decrease of protein prenylation. Inhibition of protein prenylation represents a mechanism of oAβ(42)-induced neuronal death. Supply of the isoprenoid geranylgeranyl pyrophosphate to oAβ(42)-treated neurons recovers normal protein prenylation, reduces cholesterol sequestration, and prevents Aβ-induced neurotoxicity. Significant to AD, reduced levels of protein prenylation are present in the cerebral cortex of the TgCRND8 mouse model. In conclusion, we demonstrate a significant inhibitory effect of Aβ on protein prenylation and identify SREBP-2 as a target of oAβ(42), directly linking Aβ to cholesterol homeostasis impairment.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Society for Neuroscience
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Amyloid Beta
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Cholesterol
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Alzheimer´S Disease
dc.subject.classification
Bioquímica y Biología Molecular
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
β-amyloid inhibits protein prenylation and induces cholesterol sequestration by impairing SREBP-2 cleavage
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2017-07-26T15:25:29Z
dc.identifier.eissn
1529-2401
dc.journal.volume
32
dc.journal.number
19
dc.journal.pagination
6490-6500
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Washington
dc.description.fil
Fil: Mohamed, Amany. University of Alberta; Canadá
dc.description.fil
Fil: Saavedra, Maria Lucila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Centro de Referencia Para Lactobacilos; Argentina. University of Alberta; Canadá
dc.description.fil
Fil: Di Pardo, Alba. University of Alberta; Canadá
dc.description.fil
Fil: Sipione, Simonetta. University of Alberta; Canadá
dc.description.fil
Fil: Posse de Chaves, Elena. University of Alberta; Canadá
dc.journal.title
Journal of Neuroscience
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1523/JNEUROSCI.0630-12.2012
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.jneurosci.org/content/32/19/6490
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