Overexpression of APP and SOD induces beta-amyloid deposition and oxidative stress in Down syndrome (DS) patients. Both phenomena may impair glutamate transport and decreased glutamate uptake sites have been demonstrated in patient brains at autopsy. Since alterations of APP metabolism and oxidative damage are systemic, we investigated glutamate uptake in platelets and fibroblasts from DS patients to explore whether abnormalities in this process are inherent properties of DS cells and not secondary to neurodegeneration. Glutamate uptake was significantly decreased in platelets (P<0.005 vs. control) and fibroblasts (P<0.001 vs. control) from DS patients, particularly in those with free trisomy and with mitochondrial point mutations. Systemic impairment of glutamate uptake in DS is suggested, probably related to APP overexpression and mitochondrial dysfunction. Such mechanisms may contribute to neurodegeneration and dementia development in these patients.