Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo

  • 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.

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Author:Maria Mensch, Jade Dunot, Sandy M. Yishan, Samuel S. Harris, Aline Blistein, Alban Avdiu, Paula A. PousinhaORCiD, Camilla Giudici, Marc Aurel Busche, Peter JedličkaORCiDGND, Michael WillemORCiDGND, Hélène MarieORCiD
Parent Title (English):Alzheimer's research & therapy
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Date of Publication (online):2021/07/08
Date of first Publication:2021/07/08
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/12/20
Tag:APP processing; Alzheimer; Electrophysiology; Hippocampus; Synaptic plasticity
Issue:art. 125
Article Number:125
Page Number:13
First Page:1
Last Page:13
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
This work was funded by the French Government (National Research Agency, ANR) through the “Investments for the Future” LABEX SIGNALIFE: program reference # ANR-11-LABX-0028-01 to HM and MM, the Fondation Alzheimer to HM, the Association France Alzheimer (AAP SM 2018 #1795) to HM and the University of Toronto’s PEY, an internship program for undergraduates to YSM, the UCAJEDI Investments in the Future project managed by the National Research Agency (ANR-15-IDEX-01; ComputaBrain project) to HM and the FLAG-ERA grant MILEDI by the French National Agency (ANR) contract ANR-19-HBPR-0004-02-MILEDI to HM. This work was also supported by the Deutsche Forschungsgemeinschaft (German Research Foundation) within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy) to YSM. This work was also supported by Alzheimer Forschung Initiative e.V. (15038) to PJ. SSH and MAB are supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the Medical Research Council, Alzheimer's Society and Alzheimer Research UK. MAB is further supported by a UKRI Future Leaders Fellowship (Grant Number: MR/S017003/1) and acknowledges the donors of Alzheimer's Disease Research (ADR), a program of BrightFocus Foundation (Grant Number: A2019112S).
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0