Choroid Plexus Megalin Is Involved in Neuroprotection by Serum Insulin-Like Growth Factor I

• Published in: The Journal of neuroscience Vol. 25; no. 47; pp. 10884 - 10893
• Main Authors: Carro, Eva, Spuch, Carlos, Trejo, Jose Luis, Antequera, Desire, Torres-Aleman, Ignacio
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 23.11.2005; Society for Neuroscience
• Subjects: Amyloid beta-Peptides - metabolism; Animals; Biological Transport - physiology; Brain - metabolism; Cells, Cultured; Choroid Plexus - metabolism; Cognition - physiology; Humans; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - physiology; Low Density Lipoprotein Receptor-Related Protein-2 - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity - physiology; Neurobiology of Disease; Neuroprotective Agents - metabolism; Rats; Rats, Wistar
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2909-05.2005

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.