科研之友
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摘要
Background: It is becoming increasingly evident that deficits in the cortex and hippocampus at early stages of dementia in Alzheimer%26apos;s disease (AD) are associated with synaptic damage caused by oligomers of the toxic amyloid-beta peptide (A beta 42). However, the underlying molecular and cellular mechanisms behind these deficits are not fully understood. Here we provide evidence of a mechanism by which A beta 42 affects synaptic transmission regulating neurotransmitter release. %26lt;br%26gt;Methodology/Findings: We first showed that application of 50 nM A beta 42 in cultured neurones is followed by its internalisation and translocation to synaptic contacts. Interestingly, our results demonstrate that with time, A beta 42 can be detected at the presynaptic terminals where it interacts with Synaptophysin. Furthermore, data from dissociated hippocampal neurons as well as biochemical data provide evidence that A beta 42 disrupts the complex formed between Synaptophysin and VAMP2 increasing the amount of primed vesicles and exocytosis. Finally, electrophysiology recordings in brain slices confirmed that A beta 42 affects baseline transmission. %26lt;br%26gt;Conclusions/Significance: Our observations provide a necessary and timely insight into cellular mechanisms that underlie the initial pathological events that lead to synaptic dysfunction in Alzheimer%26apos;s disease. Our results demonstrate a new mechanism by which A beta 42 affects synaptic activity.
