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

Abstract

BackgroundIt 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.Methodology/FindingsWe 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/SignificanceOur 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.

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

“…By using electron microscopy, these authors also reported that Aβ-treated neurons displayed reduced number of synaptic vesicles, especially those near the presynaptic active zones and a reduction in several presynaptic proteins (Parodi et al, 2010). Accordingly, presynaptic proteins such as SNAP-25, synaptophysin, and synaptotagmin were reduced in brains of patients with AD (Reddy et al, 2005) and in the hippocampus of Tg2576 mice 1 month after injection of Aβ into the third ventricle (Chauhan and Siegel, 2002 (Russell et al, 2012). Additionally, Aβ oligomers can alter dynamin-1, a neuron-specific GTPase that pinches off synaptic vesicles, allowing them to re-enter the synaptic vesicle pool (Kelly et al, 2005;Kelly and Ferreira, 2006).…”

“…Nevertheless, a brief exposure to a very low concentration of Aβ resulted in impairment of long term potentiation (LTP) produced by pre-synaptic defects (Russell et al, 2012).…”

Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets

“…These changes in synaptophysin in neurons of the hippocampus and association cortices correlate with changes in the cognitive decline in AD patients (Terry et al, 1991;Sze et al, 1997). Amyloid-b (Ab) peptide, which is elevated in AD brains, disrupts the interaction between synaptophysin and syb2 in vitro, leading to an increased amount of primed vesicles and exocytosis (Russell et al, 2012). The effect on synaptic vesicle endocytosis was not examined; however, other studies show that Ab disrupted synaptic vesicle endocytosis perhaps due to dynamin 1 depletion (Kelly et al, 2005;Kelly and Ferreira, 2007).…”

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

“…Enhanced presynaptic Ca 2+ , on the other hand, facilitates calpain activation by increased degradation of dynamin, a protein critical for synaptic vesicle endocytosis, and depletion of dynamin interrupts synaptic vesicle recycling (Kelly and Ferreira, 2006; Kelly et al, 2005; Watanabe et al, 2010). Alternatively, Aβ 42 , as low as 50 nM, may disrupt the formation of synaptophysin and VAMP2 complex, followed by increasing the amount of primed vesicles and exocytosis (Russell et al, 2012), although the precise mechanism for this interaction is not yet clear.…”