Protein misfolding related disorders show common cellular and molecular mechanisms included in the process of amyloidogenesis. The amyloid aggregates consist of deposits containing misfolded proteins with a beta-sheet conformation. Increasing evidences support the view that small soluble oligomeric assemblies are more directly tied to pathogenesis than the insoluble deposits. Transition metal ions emerged as crucial for neurophysiology and neuropathology, being involved in the neurotransmission and other neuronal functions. Cu(II) and Zn(II) are released at the glutamatergic synapses in the hippocampus, the place of early occurrence of amyloid beta (Aß) plaques in Alzheimer’s disease. Moreover, Zn(II) and Cu(II) dyshomeostasis has been correlated with pathologic amyloidogenesis. Epidemiological studies have linked Alzheimer’s disease (AD) and Type 2 diabetes mellitus (T2DM) and a pathophysiological relationship between two conditions has stemmed from several observations that point to the role advanced glycation end products (AGEs), metal ions, oxidative stress, insulin signalling and insulin-degrading enzyme. Both diabetes and AD are characterized by the deposition of insoluble protein aggregates: human amylin (hA) in pancreatic islets, and Aß protein in the brains respectively. In islets from T2DM patients, human amylin is co-localized with Aß. Furthermore, the receptors RAGE for AGEs and AMY-3 for hA have been shown to promote the toxicity attributed to Aß peptides. Aß and hA exert their toxicity via a secondary structure-dependent mechanism, in the absence of sequence homology. A critical issue is therefore to understand the role of environmental conditions in the kinetics of oligomerization and aggregation of peptides associated with neurodegeneration. To characterize these species and to provide insights into the implication of metals in amyloidogenesis, we studied the aggregation process in the presence of metal ions, further investigating such issue by neuronal cells treatments with different peptides. Metals appear to affect the long-term kinetic of the aggregation process and peptide toxicity.
|Titolo:||EFFECTS OF COPPER AND ZINC IONS ON LONG-TERM KINETICS OF AGGREGATION AND TOXICITY OF AMYLOIDOGENIC PEPTIDES|
|Data di pubblicazione:||2013|
|Appare nelle tipologie:||4.1 Contributo in Atti di convegno|