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A eta-alpha and A eta-beta peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo

Mensch, M; Dunot, J; Yishan, SM; Harris, SS; Blistein, A; Avdiu, A; Pousinha, PA; ... Marie, H; + view all (2021) A eta-alpha and A eta-beta peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo. Alzheimer's Research & Therapy , 13 (1) , Article 125. 10.1186/s13195-021-00860-1. Green open access

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Abstract

Background: Amyloid precursor protein (APP) processing is central to Alzheimer’s disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη–α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo. Methods: With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-β peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology. Results: We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-β, like Aη–α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη–α in vivo. Conclusions: These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.

Type: Article
Title: A eta-alpha and A eta-beta peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/s13195-021-00860-1
Publisher version: http://dx.doi.org/10.1186/s13195-021-00860-1
Language: English
Additional information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Keywords: Clinical Neurology, Neurosciences, APP processing, Synaptic plasticity, Electrophysiology, Hippocampus, Alzheimer, AMYLOID-PRECURSOR-PROTEIN, SYNAPTIC PLASTICITY, ALZHEIMERS-DISEASE, RANDOMIZED-TRIAL, MOUSE MODEL, VERUBECESTAT, OLIGOMERS, DYNAMICS, RELEASE
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10132490
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