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Choroid plexus megalin is involved in neuroprotection by serum insulin-like growth factor I

AuthorsCarro, Eva; Spuch, Carlos; Trejo, José L. ; Antequera, D.; Torres Alemán, Ignacio
Issue Date2005
PublisherSociety for Neuroscience
CitationJournal of Neuroscience 25: 10884- 10893 (2005)
AbstractThe 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 β (Aβ) by modulating transport/production of Aβ 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 Aβ carriers. By manipulating choroid plexus megalin levels through viral-directed overexpression and RNA interference, we observed that megalin mediates IGF-I-induced clearance of Aβ 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. Copyright © 2005 Society for Neuroscience.
Identifiersdoi: 10.1523/JNEUROSCI.2909-05.2005
issn: 0270-6474
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