The peptidase nardilysin is involved in degradation of neuropeptides and limited intracellular proteolysis. Recent reports point to an involvement of nardilysin in the pathophysiology of Alzheimer's disease. Nardilysin enhances the alpha-secretase activity of the disintegrin and metalloproteases (ADAMs) 10 and 17, thereby possibly contributing to reduced generation of amyloidogenic fragments from the amyloid precursor protein. A prerequisite for the alpha-secretase-stimulating effect of nardilysin on the activity of ADAMs in vivo is cellular co-expression of nardilysin with ADAM10 and/or ADAM17. We immunolocalised nardilysin, ADAM10, and ADAM17 in cortical regions of normal aged brain, in Alzheimer's disease, and in Down syndrome brains and counted the number of protease-expressing neurons. A considerable portion of neurons co-express nardilysin together with either ADAM10 or ADAM17. Compared to controls, in Alzheimer's disease and in Down syndrome brains there is a decreased cellular expression of all three antigens, and a reduction in the number of those neurons that co-express nardilysin with ADAM10 or with ADAM17. Our data are consistent with the notion that the proposed alpha-secretase-enhancing activity of nardilysin might play a role in human brain pathology.