3.Pore-Forming Neurotoxin-Like Mechanism for Aβ Oligomer-Induced Synaptic Failure医学电子书.pdf

Pore-Forming Neurotoxin-Like Mechanism for Ab Oligomer-Induced Synaptic Failure Luis G. Aguayo, Jorge Parodi, Fernando J. Sepúlveda, and Carlos Opazo Abstract Cortical and hippocampal synapse densities are reduced in Alzheimer’s disease (AD), and this strongly correlates with memory dysfunction. It is now believed that these changes in neuronal networking occur at the onset of AD and may lead to the neuronal loss displayed in later stages of the disease, which is characterized by severe cognitive and behavioral impairments. Mounting evidence indicates that amyloid-b (Ab ) oligomers are responsible for synaptic disconnections and neuronal death. One of the main consequences of Ab oligomers interaction with neurons is an increase in intracellular Ca2+ concentration that could, when large enough, cause a marked altera- tion in ionic homeostasis. It has also been postulated that Ca2+ influx occurs when Ab oligomers induce the opening of Ca2+ channels or the disruption of the plasma mem- brane. We recently found that the effects of Ab oligomers on synaptic transmission are similar to pore-forming toxins, such as a -latrotoxin, a neurotoxin from the black widow spider. Here, we discuss evidence supporting a neurotoxin-like mechanism for the effects induced by Aboligomers on neuronal membranes, which could explain the alterations in the functionality of synapses in the central nervous system in AD that leads to major neurodegeneration with time of exposure to Aboligomers. Abbreviations Ab: amyloid-b peptide, AD: Alzheimer’s disease; a -LTX: a -latrotoxin; Ab PP: amyloid-b protein precursor; Ca2+: calcium ; LTP: long-term potentiation; pS: picoSiemen 1 Increase in Soluble Ab Oligomers is a Key Factor for Alzheimer’s Disease Onset One of the main histopathological features of Alzheimer’s disease (AD) is the presence of extracellular proteinaceous deposits in the brain, i