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One of the possible mechanisms involved in beta-amyloid (Abeta)-induced neuronal damage is blood-cerebrospinal fluid barrier dysfunction. Recently, we have demonstrated that Alzheimer patients have an elevated expression of Abeta in the choroid plexus (CP), where it could impair the physiological functions of CP epithelium. We investigated whether these alterations were mediated by mitochondrial dysfunction, a common early pathomechanism in Alzheimer's disease. Our main observations were: high Abeta levels; increased nitric oxide levels; impairment of the activity and assembly of mitochondrial respiratory chain complexes I and IV; and a significant increase in reactive oxygen species and caspase expression in CP epithelial cells treated with Abeta. Our results also demonstrate a direct relationship between Abeta toxicity, increased expression of matrix metalloproteinase-9, and blood-cerebrospinal fluid barrier disruption. We propose a sequence of pathological steps that link Abeta accumulation in CP epithelium with an enhanced nitric oxide production, mitochondrial dysfunction, and up-regulation of matrix metalloproteinase-9, which ultimately lead to cell death, and probably to CSF barrier dysfunction.

Insulin-like growth factor I (IGF-I), a neuroprotective factor with a wide spectrum of actions in the adult brain is involved in the pathogenesis of Alzheimer's disease (AD). Circulating levels of IGF-I change in AD patients and are implicated in the clearance of brain amyloid beta (Lambda beta) complexes. To investigate this hypothesis, we screened the IGF-I gene for various well known single nucleotide polymorphisms (SNPs) covering % of the gene variability in a population of 2352 individuals. Genetic analysis indicated different distribution of genotypes of 1 single nucleotide polymorphism., and 1 extended haplotype in the AD population compared with healthy control subjects. In particular, the frequency of rs972936 GC, genotype was significantly greater in AD patients than in control subjects (63% vs. 55%). The rs972936 GG genotype was associated with an increased risk for disease, independently of apolipoprotein E genotype, and with enhanced circulating levels of IGF-I. These findings suggest that polymorphisms within the IGF-I gene could infer greater risk for AD through their effect on ICE-I levels, and confirm the physiological role IGF-I in the pathogenesis of AD. (C) 2011 IBRO All rights reserved.