P1–213: Choroid plexus amyloid–β deposits disturb IGF–I signaling in blood–cerebrospinal fluid barrier

The formation of insoluble aggregates of Aβ within the brain extracellular fluid is considered to be a critical event in Alzheimer's disease (AD). This accumulation includes overproduction in the brain, inadequate metabolic clearance within the brain, or an improper balance of import and export Aβ and Aβ–related molecules at the brain barriers. Choroid plexus expresses high levels of IGF–IR and megalin that are implicated in the correct physiological function of the barrier. We focused our attention in neuroprotection by IGF–I on choroid plexus megalin, and the relationship between the IGF–I/IGF–IR system and megalin. To investigate the possible effects of Aβ deposits in choroid plexus, we have used tissue and CSF samples from AD patients. These results were also compared in vitro using primary cultures from choroid plexus epithelial cells treated with the different peptides. We have detected accumulations of Aβ inside of choroid plexus epithelium from AD patients. We have observed that Aβ directly blocked the IGF–I signal at different steps, and explain how Aβ accumulation could damage the correct function of choroid plexus, where IGF–I signal pathway is crucial in neuroprotection of choroid plexus and brain. These novel findings between Aβ accumulation and IGF–I signaling in choroid plexus suggest that Aβ deposits alter the correct function of choroid plexus at several levels: interrupting IGF–I signal pathway, blocking transcytosis mechanisms induced by megalin, and reducing the secretion of TTR into CSF. These data verify the crucial link between megalin and IGF–I, and the importance of both pathways in normal function of choroid plexus. We conclude that the IGF–IR/megalin pathway, at the choroid plexus level, possess a strong functional relationship and it is an interesting target to effective therapeutical treatment of AD.