Beschreibung:
Amyloid beta (Aβ) is a peptide derived from proteolytic cleavage of amyloid precursor protein (APP) by β and γ-secretases. While multiple isoforms of this protein are present in the human brain, to date research on Aβ has focused on the pathological effect of the predominant Aβ1-42 species as the major component of senile plaques present in Alzheimer´s disease brains. More recently, the discovery of Aβ presence at low levels in normal healthy brains has prompted investigation of its physiological function. These new findings have reported a previously unknown positive regulatory effect of Aβ on long-term potentiation (LTP) and memory, suggesting its beneficial physiological role when present in low concentrations in the brain (Puzzo et al., 2008;Puzzo et al., 2011). Interestingly, the N-terminal Aβ fragment has been suggested to be particularly effective in this neuromodulation (Lawrence et al., 2014;Richter et al., 2018). Despite of several hints pointing to role of Aβ and other APP-derived fragments in the regulation of presynaptic function, a systematic investigation has not been performed yet. To close this gap, we explored the potential role of physiological concentrations of APP/Aβ-derived fragments in the modulation of presynaptic activity and the molecular and cellular mechanisms involved in this process. We identified distinct effects of N- and C-terminal part of Aβ1-42 on recycling of synaptic vesicles (SVs) in cultured primary neurons. While the N-terminal Aβ fragment (Aβ1-16) enhanced synaptic transmission via an increase in the fraction of recycling pool of SVs, the C- terminal fragment (Aβ17-42) had no effect. The observed enhancement of SV recycling driven by the N-terminal Aβ fragment required functional alpha 7 nicotinic acetylcholine receptors (α7nAchRs). It was completely blocked by α-Bungarotoxin (BgTx), a selective antagonist of these receptors, and was absent in neurons from α7nAchRs knockout mice. Our data suggested that Aβ acts as a positive allosteric modulator of α7nAchRs rather than an ...