EFFECT OF TRANSITION METALS IN SYNAPTIC DAMAGE INDUCED BY AMYLOID BETA PEPTIDE

The amyloid (beta-peptide (A beta), which is thought to be the major cause of Alzheimer's disease (AD), is known to be capable of aggregating in different states: soluble monomers and oligomers, and insoluble aggregates. The A beta aggregation state as well as its toxicity has been related to the interaction between the peptide and transition metals such as iron and copper. However, this relationship, as well as the effects of A beta on the synaptic endings, is not fully understood. The aggregation states of A beta in the presence of iron and copper, as well as their effects on synaptic viability and signaling were investigated in this work. During acute incubation treatments (5 min-4 h), A beta/metal impaired mitochondrial function to the same extent as has been observed with the metal alone. However, in the presence of A beta/iron (10 and 50 mu M), plasma membrane integrity was disrupted to a greater extent than when generated by either iron or A beta alone, indicating that the membrane constitutes the first target of synaptic injury. Akt activation by A beta/iron was evident after 5 min of incubation and was higher than that observed in the presence of the metal alone. This activation was barely detected after 4 h of incubation, demonstrating that there is no correlation between the extent of synaptic damage and the activation of this kinase. Extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation profile was different from that observed for Akt. Accordingly, the presence of A beta/metal could differentially modulate the activity of these kinases. This work shows evidence of the initial events locally triggered at the synapse by A beta and transition metals. As synapses have been proposed as the starting point of A beta/metal-triggered events, the characterization of early mechanisms occurring in models that mimic AD could be important for the search of unexplored therapeutics tools. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.