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-β peptide (Aβ42). However, the underlying molecular and cellular mechanisms behind these deficits are not fully understood. Here we provide evidence of a mechanism by which Aβ42 affects synaptic transmission regulating neurotransmitter release.


RESULTS
We first showed that application of 50 nM Aβ42 in cultured neurones is followed by its internalisation and translocation to synaptic contacts. Interestingly, our results demonstrate that with time, Aβ42 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 Aβ42 disrupts the complex formed between Synaptophysin and VAMP2 increasing the amount of primed vesicles and exocytosis. Finally, electrophysiology recordings in brain slices confirmed that Aβ42 affects baseline transmission.


CONCLUSIONS
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 Aβ42 affects synaptic activity.
School of Biological Sciences, Royal Holloway University London, Surrey, United Kingdom.
Claire L
CL
Russell
Sophia
S
Semerdjieva
Ruth M
RM
Empson
Brian M
BM
Austen
Philip W
PW
Beesley
Pavlos
P
Alifragis
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004594:Electrophysiology / Q000379:methods; D005089:Exocytosis; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission; D016708:Synaptophysin / Q000378:metabolism*; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D018377:Neurotransmitter Agents; D010455:Peptides; D016708:Synaptophysin; C494706:Vamp2 protein, rat; D050988:Vesicle-Associated Membrane Protein 2