Abeta accumulation in choroid plexus is associated with mitochondrial-induced apoptosis

Abstract

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.