PoreForming Neurotoxin-Like Mechanism for Aβ Oligomer-Induced Synaptic Failure (original) (raw)

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-β (Aβ) oligomers are responsible for synaptic disconnections and neuronal death. One of the main consequences of Aβ oligomers interaction with neurons is an increase in intracellular Ca2+ concentration that could, when large enough, cause a marked alteration in ionic homeostasis. It has also been postulated that Ca2+ influx occurs when Aβ oligomers induce the opening of Ca2+ channels or the disruption of the plasma membrane. We recently found that the effects of Aβ oligomers on synaptic transmission are similar to pore-forming toxins, such as α-latrotoxin, a neurotoxin from the black widow spider. Here, we discuss evidence supporting a neurotoxin-like mechanism for the effects induced by Aβ oligomers 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 Aβ oligomers.

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