NUMEROUS lines of evidence suggest that some of the neurotoxicity associated with Alzheimer's disease (AD) is due to proteolytic fragments of the amyloid precursor protein (APP). Most research has focused on the amyloid β peptide (A β). However, the possible role of other cleaved products of APP is less clear. In this study, the effects of a recombinant carboxy terminal 105 amino acid (CT105) fragment of APP on the calcium uptake by endoplasmic reticulum Mg2+-Ca2+ATPase, the major mechanism for sequestering calcium in this orgenelle, were investigated. We found that CT 105 is a potent inhibitor of Mg2+-Ca2+ATPase of endoplasmic reticulum, whereasAβ shows no effect. These results demonstrate that CT 105 inhibits the ability of brain microsomes to sequester calcium and suggest that this inhibitory effect of CT 105 may contribute to disruption of intracellular calcium concentration, possibly being involved in inducing the neural toxicity characteristic of AD.NeuroRepor t9: 3875–3879 © 1998 Lippincott Williams & Wilkins.