Amyloid-β-Acetylcholinesterase complexes potentiate neurodegenerative changes induced by the Aβ peptide. Implications for the pathogenesis of Alzheimer's disease

The presence of amyloid-beta (A beta) deposits in selected brain regions is a hallmark of Alzheimer's disease (AD). The amyloid deposits have chaperone molecules which play critical roles in amyloid formation and toxicity. We report here that treatment of rat hippocampal neurons with A beta-acetylcholinesterase (A beta-AChE) complexes induced neurite network dystrophia and apoptosis. Moreover, the A beta-AChE complexes induced a sustained increase in intracellular Ca2+ as well as a loss of mitochondrial membrane potential. The A beta-AChE oligomers complex also induced higher alteration of Ca2+ homeostasis compared with A beta-AChE fibrillar complexes. These alterations in calcium homeostasis were reversed when the neurons were treated previously with lithium, a GSK-3 beta inhibitor; Wnt-7a ligand, an activator for Wnt Pathway; and an N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801), demonstrating protective roles for activation of the Wnt signaling pathway as well as for NMDA-receptor inhibition. Our results indicate that the A beta-AChE complexes enhance A beta-dependent deregulation of intracellular Ca2+ as well as mitochondrial dysfunction in hippocampal neurons, triggering an enhanced damage than A beta alone. From a therapeutic point of view, activation of the Wnt signaling pathway, as well as NMDAR inhibition may be important factors to protect neurons under A beta-AChE attack.