The Relevance of Amyloid β-Calmodulin Complexation in Neurons and Brain Degeneration in Alzheimer's Disease

Intraneuronal amyloid beta (A beta) oligomer accumulation precedes the appearance of amyloid plaques or neurofibrillary tangles and is neurotoxic. In Alzheimer's disease (AD)-affected brains, intraneuronal A beta oligomers can derive from A beta peptide production within the neuron and, also, from vicinal neurons or reactive glial cells. Calcium homeostasis dysregulation and neuronal excitability alterations are widely accepted to play a key role in A beta neurotoxicity in AD. However, the identification of primary A beta-target proteins, in which functional impairment initiating cytosolic calcium homeostasis dysregulation and the critical point of no return are still pending issues. The micromolar concentration of calmodulin (CaM) in neurons and its high affinity for neurotoxic A beta peptides (dissociation constant approximate to 1 nM) highlight a novel function of CaM, i.e., the buffering of free A beta concentrations in the low nanomolar range. In turn, the concentration of A beta-CaM complexes within neurons will increase as a function of time after the induction of A beta production, and free A beta will rise sharply when accumulated A beta exceeds all available CaM. Thus, A beta-CaM complexation could also play a major role in neuronal calcium signaling mediated by calmodulin-binding proteins by A beta; a point that has been overlooked until now. In this review, we address the implications of A beta-CaM complexation in the formation of neurotoxic A beta oligomers, in the alteration of intracellular calcium homeostasis induced by A beta, and of dysregulation of the calcium-dependent neuronal activity and excitability induced by A beta.

Automated summary

This study addresses the implications of Aβ-CaM complexation in the formation of neurotoxic Aβ oligomers, the alteration of intracellular calcium homeostasis induced by Aβ, and the dysregulation of calcium-dependent neuronal activity and excitability induced by Aβ.