Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I.
The involvement of circulating insulin-like growth factor I (IGF-I) in the beneficial effects of physical exercise on the brain makes this abundant serum growth factor a physiologically relevant neuroprotective signal. However, the mechanisms underlying neuroprotection by serum IGF-I remain primarily unknown. Among many other neuroprotective actions, IGF-I enhances clearance of brain amyloid beta (Abeta) by modulating transport/production of Abeta carriers at the blood-brain interface in the choroid plexus. We found that physical exercise increases the levels of the choroid plexus endocytic receptor megalin/low-density lipoprotein receptor-related protein-2 (LRP2), a multicargo transporter known to participate in brain uptake of Abeta carriers. By manipulating choroid plexus megalin levels through viral-directed overexpression and RNA interference, we observed that megalin mediates IGF-I-induced clearance of Abeta and is involved in IGF-I transport into the brain. Through this dual role, megalin participates in the neuroprotective actions of IGF-I including prevention of tau hyperphosphorylation and maintenance of cognitive function in a variety of animal models of cognitive loss. Because we found that in normal aged animals, choroid plexus megalin/LRP2 is decreased, an attenuated IGF-I/megalin input may contribute to increased risk of neurodegeneration, including late-onset Alzheimer's disease.
Carro
Eva
E
Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain.
Spuch
Carlos
C
Trejo
Jose Luis
JL
Antequera
Desiré
D
Torres-Aleman
Ignacio
I
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002831:Choroid Plexus / Q000378:metabolism*; D003071:Cognition / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000502:physiology; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D018696:Neuroprotective Agents; D007334:Insulin-Like Growth Factor I