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

Mensch, Maria; Dunot, Jade; Yishan, Sandy M.; Harris, Samuel S.; Blistein, Aline; Avdiu, Alban; Pousinha, Paula A.; Giudici, Camilla; Busche, Marc Aurel; Jedlicka, Peter; Willem, Michael und Marie, Helene (2021): A eta-alpha and A eta-beta peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo. In: Alzheimers Research & Therapy, Bd. 13, Nr. 1, 125

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 eta-secretase-derived peptides (A eta) and revealed that A eta-alpha, the longest form of A eta produced by eta-secretase and alpha-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 A eta-alpha and the shorter A eta-beta 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 A eta-beta, like A eta-alpha, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by A eta-alpha in vivo. Conclusions These results provide novel insights into the functional role of the recently discovered eta-secretase-derived products and suggest that A eta peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198