Effects of trace metals on the conformational changes of amyloidogenic proteins and their neurotoxicity

摘要

Conformational changes of Alzheimer's ?-amyloid protein (A?P) enhance its neurotoxicity, and finally lead to Alzheimer's pathogenesis. Recent studies have suggested that a common mechanism is based on the diverse diseases termed “conformational diseases”, including other neurodegenerative diseases such as prion diseases, Parkinson's disease, and triplet-repeat disease. These diseases share similarity in the formation of ?-sheet containing amyloid fibrils by disease-related proteins including prion protein, α-synuclein, polyglutamine, and the introduction of apoptotic degeneration. Trace elements can bind to these proteins and play crucial roles in their conformational changes. Aluminum is suspected to be an environmental risk factor of Alzheimer's disease. Prion protein is a copper binding protein and is believed to be implicated in copper homeostasis. We have investigated effects of aluminum, zinc, copper and other metals on the conformational changes and neurotoxicity of A?P or prion protein fragment peptide. Although the molecular mechanism of neurodegeneration induced by these conformational disease-related proteins remains elusive, these proteins have the ability to directly incorporate into membranes directly and to form calcium-permeable ion channels. Our and other numerous studies have revealed that A?P cause the abnormal elevation of intracellular calcium levels. We review here the current understanding of the pathology of the conformational diseases based on the metal-binding to disease-related proteins and on the disruption of calcium homeostasis through amyloid channels.