Effect of transition metals and amy loid beta peptide on synaptic injury and signaling

ROMINA MARÍA URANGA, NORMA MARÍA GIUSTO, AND GABRIELA ALEJANDRA SALVADOR

NEUROSCIENCE

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2010 vol. 170 p. 381 - 389

0306-4522

Abstract—The amyloid
-peptide (A
), which is thought to bethe major cause of Alzheimer’s disease (AD), is known to becapable of aggregating in different states: soluble monomersand oligomers, and insoluble aggregates. The A
aggrega-tion state as well as its toxicity has been related to theinteraction between the peptide and transitionmetals such asiron and copper. However, this relationship, as well as theeffects of A
on the synaptic endings, is not fully understood.The aggregation states of A
in the presence of iron andcopper, as well as their effects on synaptic viability andsignaling were investigated in this work. During acute incu-bation treatments (5 min–4 h), A
/metal impaired mitochon-drial function to the same extent as has been observed withthe metal alone. However, in the presence of A
/iron (10 and50 M), plasma membrane integrity was disrupted to agreater extent than when generated by either iron or A
alone, indicating that the membrane constitutes the first tar-get of synaptic injury. Akt activation by A
/iron was evidentafter 5 min of incubation and was higher than that observedin the presence of the metal alone. This activation was barelydetected after4hof incubation, demonstrating that there isno correlation between the extent of synaptic damage and theactivation of this kinase. Extracellular signal-regulated ki-nases 1 and 2 (ERK1/2) activation profile was different fromthat observed for Akt. Accordingly, the presence of A
/metalcould differentially modulate the activity of these kinases.This work shows evidence of the initial events locally trig-gered at the synapse by A
and transition metals. As syn-apses have been proposed as the starting point of A
/metal-triggered events, the characterization of early mechanismsoccurring in models that mimic AD could be important for thesearch of unexplored therapeutics tools. © 2010 IBRO. Pub-lished by Elsevier Ltd. All rights reserved.