Research article

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

Margarita C Dinamarca^* , Juan P Sagal^* , Rodrigo A Quintanilla^* , Juan A Godoy , Macarena S Arrázola and Nibaldo C Inestrosa

Centro de Regulación Celular y Patología "Joaquín V. Luco" (CRCP), Instituto Milenio MIFAB, Centro de Envejecimiento y Regeneración (CARE), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, 8331010 Santiago, Chile

author email corresponding author email* Contributed equally

Molecular Neurodegeneration 2010, 5:4doi:10.1186/1750-1326-5-4

Published:	18 January 2010

Abstract

The presence of amyloid-β (Aβ) 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 Aβ-acetylcholinesterase (Aβ-AChE) complexes induced neurite network dystrophia and apoptosis. Moreover, the Aβ-AChE complexes induced a sustained increase in intracellular Ca²⁺ as well as a loss of mitochondrial membrane potential. The Aβ-AChE oligomers complex also induced higher alteration of Ca²⁺ homeostasis compared with Aβ-AChE fibrillar complexes. These alterations in calcium homeostasis were reversed when the neurons were treated previously with lithium, a GSK-3β 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 Aβ-AChE complexes enhance Aβ-dependent deregulation of intracellular Ca²⁺ as well as mitochondrial dysfunction in hippocampal neurons, triggering an enhanced damage than Aβ 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 Aβ-AChE attack.