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dc.contributor.authorBolós, M.-
dc.contributor.authorFernández, Silvia Venero-
dc.contributor.authorTorres Alemán, Ignacio-
dc.identifierdoi: 10.1074/jbc.M109.096594-
dc.identifierissn: 0021-9258-
dc.identifier.citationJournal of Biological Chemistry 285: 17693- 17700 (2010)-
dc.description.abstractReduced 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.publisherAmerican Society for Biochemistry and Molecular Biology-
dc.titleOral administration of a GSK3 inhibitor increases brain insulin-like growth factor I levels-
dc.description.versionPeer Reviewed-
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