Oral administration of a GSK3 inhibitor increases brain insulin-like growth factor I levels.
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.
Bolós
Marta
M
Cajal Institute, Consejo Superior de Investigaciones Científicas, and Ciberned, Madrid 28002, Spain.
Fernandez
Silvia
S
Torres-Aleman
Ignacio
I
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004285:Dogs; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018110:Receptors, Lipoprotein / Q000378:metabolism
D009414:Nerve Growth Factors; D018110:Receptors, Lipoprotein; D007334:Insulin-Like Growth Factor I; D038362:Glycogen Synthase Kinase 3