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The Journal of Neuroscience, November 23, 2005, 25(47):10884-10893; doi:10.1523/JNEUROSCI.2909-05.2005

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

Eva Carro, ^* Carlos Spuch, ^* Jose Luis Trejo, Desiré Antequera, and Ignacio Torres-Aleman

Laboratory of Neuroendocrinology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain

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 (A) by modulating transport/production of A 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 A carriers. By manipulating choroid plexus megalin levels through viral-directed overexpression and RNA interference, we observed that megalin mediates IGF-I-induced clearance of A 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.

Key words: megalin-LRP2; insulin-like growth factor I receptor; choroid plexus; amyloidosis; Alzheimer's disease; physical exercise

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Received July 14, 2005; revised September 2, 2005; accepted October 2, 2005.

This article has been cited by other articles:

				C. Ohlsson, S. Mohan, K. Sjogren, A. Tivesten, J. Isgaard, O. Isaksson, J.-O. Jansson, and J. Svensson The Role of Liver-Derived Insulin-Like Growth Factor-I Endocr. Rev., August 1, 2009; 30(5): 494 - 535. [Abstract] [Full Text] [PDF]

				I. Torres-Aleman Mouse Models of Alzheimer's Dementia: Current Concepts and New Trends Endocrinology, December 1, 2008; 149(12): 5952 - 5957. [Abstract] [Full Text] [PDF]

				C. Lopez-Lopez, M. O. Dietrich, F. Metzger, H. Loetscher, and I. Torres-Aleman Disturbed Cross Talk between Insulin-Like Growth Factor I and AMP-Activated Protein Kinase as a Possible Cause of Vascular Dysfunction in the Amyloid Precursor Protein/Presenilin 2 Mouse Model of Alzheimer's Disease J. Neurosci., January 24, 2007; 27(4): 824 - 831. [Abstract] [Full Text] [PDF]

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