Regulation of presynaptic plasticity by APP/Aβ-derived fragments

Language
en
Document Type
Doctoral Thesis
Issue Date
2021-06-07
Issue Year
2021
Authors
Anni, Daniela
Editor
Abstract

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 activator, increasing nicotine-evoked Ca2+ currents, as well as the phosphorylation levels of CREB at serine 133. Furthermore, Aβ attenuated synaptic depletion of SV recycling pool in response to multiple field stimulations, thus regulating the availability of SVs for neurotransmission. This was connected with an increase in the calcineurin activity and changes in the phosphorylation of synapsin 1 at serine 551, 603 and 9. Intriguingly, Aβ-increased SV recycling also required N-type Ca2+ channels, suggesting a functional link between α7nAChRs activation and N-type modulation. In conclusion, our findings demonstrate a unique role for the N-terminal Aβ-fragment (Aβ1-16) as an enhancer of presynaptic SV cycling through regulation of SV availability via changes in phosphorylation status of synapsin 1. Moreover, we uncovered a molecular pathway behind this process involving calcineurin/CDK5, PKA and/or CAMKI/IV, and CAMKII signaling. A failure of precise regulation of SV recycling upon disruption of normal Aβ metabolism may contribute to synaptic dysfunction occurring at the early stage of Alzheimer’s disease and the pharmacological strategies targeting this process might open up the possibilities for future therapies in this condition.

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