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dc.contributor.author | Bolós, M. | - |
dc.contributor.author | Fernández, Silvia Venero | - |
dc.contributor.author | Torres Alemán, Ignacio | - |
dc.date.accessioned | 2012-11-27T09:48:43Z | - |
dc.date.available | 2012-11-27T09:48:43Z | - |
dc.date.issued | 2010 | - |
dc.identifier | doi: 10.1074/jbc.M109.096594 | - |
dc.identifier | issn: 0021-9258 | - |
dc.identifier.citation | Journal of Biological Chemistry 285: 17693- 17700 (2010) | - |
dc.identifier.uri | http://hdl.handle.net/10261/61219 | - |
dc.description.abstract | Reduced brain input of serum insulin-like growth factor I (IGF-I), a potent neurotrophic peptide, may be associated with neurodegenerative processes. Thus, analysis of the mechanisms involved in passage of blood-borne IGF-I into the brain may shed light onto pathological mechanisms in neurodegeneration and provide new drug targets. A site of entrance of serum IGF-I into the brain is the choroid plexus. The transport mechanism for IGF-I in this specialized epithelium involves the IGF-I receptor and the membrane multicargo transporter megalin/LRP2. We have now analyzed this process in greater detail and found that the IGF-I receptor interacts with the transmembrane region of megalin, whereas the perimembrane domain of megalin is required for IGF-I internalization. Furthermore, a GSK3 site within the Src homology 3 domain of the C-terminal region of megalin is a key regulator of IGF-I transport. Thus, inhibition of GSK3 markedly increased internalization of IGF-I, whereas mutation of this GSK3 site abrogated this increase. Notably, oral administration of a GSK3 inhibitor to adult wild-type mice or to amyloid precursor protein/presenilin 1 mice modeling Alzheimer amyloidosis significantly increased brain IGF-I content. These results indicate that pharmacological modulation of IGF-I transport by megalin may be used to increase brain availability of serum IGF-I. Interestingly, GSK3 inhibitors such as those under development to treat Alzheimer disease may show therapeutic efficacy in part by increasing brain IGF-I levels, an effect already reported for other neuroprotective compounds. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. | - |
dc.language.iso | eng | - |
dc.publisher | American Society for Biochemistry and Molecular Biology | - |
dc.rights | closedAccess | - |
dc.title | Oral administration of a GSK3 inhibitor increases brain insulin-like growth factor I levels | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1074/jbc.M109.096594 | - |
dc.date.updated | 2012-11-27T09:48:44Z | - |
dc.description.version | Peer Reviewed | - |
dc.identifier.pmid | 20351102 | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.cerifentitytype | Publications | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.grantfulltext | none | - |
item.openairetype | artículo | - |
item.fulltext | No Fulltext | - |
item.languageiso639-1 | en | - |
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