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Carro E.,Hospital 12 Of Octubre | Vargas T.,Hospital 12 Of Octubre | Antequera D.,CIBER ISCIII | Ugalde C.,Hospital 12 Of Octubre | Spuch C.,Rare Disorders Biomedical Research Center
Journal of Biomedicine and Biotechnology | Year: 2010

Histologically, Alzheimer's disease (AD) is characterized by senile plaques and cerebrovascular amyloid deposits. In previous studies we demonstrated that in AD patients, amyloid- (Aβ) peptide also accumulates in choroid plexus, and that this process is associated with mitochondrial dysfunction and epithelial cell death. However, the molecular mechanisms underlying Aβ accumulation at the choroid plexus epithelium remain unclear. Aβ clearance, from the brain to the blood, involves A carrier proteins that bind to megalin, including gelsolin, a protein produced specifically by the choroid plexus epithelial cells. In this study, we show that treatment with gelsolin reduces Aβ -induced cytoskeletal disruption of blood-cerebrospinal fluid (CSF) barrier at the choroid plexus. Additionally, our results demonstrate that gelsolin plays an important role in decreasing Aβ -induced cytotoxicity by inhibiting nitric oxide production and apoptotic mitochondrial changes. Taken together, these findings make gelsolin an appealing tool for the prophylactic treatment of AD. © 2010 Teo Vargas et al.

Vargas T.,Hospital 12 Of Octubre | Vargas T.,CIBER ISCIII | Ugalde C.,Hospital 12 Of Octubre | Ugalde C.,Rare Disorders Biomedical Research Center | And 14 more authors.
Neurobiology of Aging | Year: 2010

One of the possible mechanisms involved in β-amyloid (Aβ)-induced neuronal damage is blood-cerebrospinal fluid barrier dysfunction. Recently, we have demonstrated that Alzheimer patients have an elevated expression of Aβ 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 Aβ 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 Aβ. Our results also demonstrate a direct relationship between Aβ toxicity, increased expression of matrix metalloproteinase-9, and blood-cerebrospinal fluid barrier disruption. We propose a sequence of pathological steps that link Aβ 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. © 2008 Elsevier Inc.

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