科研之友
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摘要
It is well accepted that cortical and hippocampal synaptic densities are reduced in Alzheimer's disease (AD). These alterations in neuronal networking occur at the very 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. Many studies suggest that amyloid-beta (A beta) oligomers are responsible for synaptic disconnections and neuronal death. The effects of A beta in different brain regions are pleotropic, thus suggesting a common mechanism for toxicity. One potential site for this mechanism of toxicity is the neuronal membrane. It is recognized that A beta can associate to the plasma membrane and induce the formation of pores after the interaction with lipids like GM1 and cholesterol, and proteins such as APP and NMDA receptors. After this early event, the membrane increases its permeability allowing the influx of small ions and larger molecules. Thus, one of the main toxic consequences of A beta oligomer interaction with neurons is an increase in intracellular Ca2+ concentration that causes alterations in ionic homeostasis. It has been proposed that A beta perforates the membrane similarly to pore-forming toxins producing a series of effects that include synaptic failure and cell death. These actions of A beta appear to be potentiated by neuroinflammation, which results in a series of effects that, when prolonged, will affect membrane integrity, pore formation and cellular homeostasis. Here, we will review the most recent data on A beta actions at the membrane level and how its relationship with neuroinflammation could further potentiate brain impairment in AD. The notion of having drugs acting with dual inhibitory actions, inhibition of membrane damage and inflammation, could serve as a starting conceptual point for the development of new therapies for the disease.
- 出版日期2016
