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

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