Amyloid beta-peptides (A beta) are a major hallmark of Alzheimer's disease (AD) and their neurotoxicity develop with cytosolic calcium dysregulation. On the other hand, calmodulin (CaM), a protein which plays a major multifunctional role in neuronal calcium signaling, has been shown to be involved in the regulation of non-amyloidogenic processing of amyloid beta precursor protein (APP). Using fluorescent 6-bromoacetyl-2-dimethylaminonaphthalene derivatives of CaM, Badan-CaM, and human amyloid beta(1-42) HiLyte (TM)-Fluor555, we show in this work that A beta binds with high affinity to CaM through the neurotoxic A beta 25-35 domain. In addition, the affinity of A beta for calcium-saturated CaM conformation is approximately 20-fold higher than for CaM conformation in the absence of calcium (apo-CaM). Moreover, the value of K-d of 0.98 +/- 0.11 nM obtained for A beta 1-42 dissociation from CaM saturated by calcium points out that CaM is one of the cellular targets with highest affinity for neurotoxic A beta peptides. A major functional consequence of A beta-CaM interaction is that it slowdowns A beta fibrillation. The novel and high affinity interaction between calmodulin and A beta shown in this work opens a yet-unexplored gateway to further understand the neurotoxic effect of A beta in different neural cells and also to address the potential of calmodulin and calmodulin-derived peptides as therapeutic agents in AD. (C) 2017 Elsevier Inc. All rights reserved.