Amyloid-β Acts as a Regulator of Neurotransmitter Release Disrupting the Interaction between Synaptophysin and VAMP2

Background: It is becoming increasingly evident that deficits in the cortex and hippocampus at early stages of dementia in Alzheimer'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. 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. 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's disease. Our results demonstrate a new mechanism by which A beta 42 affects synaptic activity.