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 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 give 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.

Identification of binding partners that facilitate membrane‐type 5 matrix metalloproteinase (MT5‐MMP) processing of amyloid precursor protein

“…Following the Willem et al, 2015). Although recombinantly expressed Aη-β was initially reported to not lower hippocampal long-term potentiation nor suppress the activity of hippocampal neurons (Willem et al, 2015), it was subsequently reported by the same researchers that chemically synthesized Aη-β impaired hippocampal long-term potentiation and inhibited neuronal activity (Mensch et al, 2021). In addition, because CTF-η by can processed by β-secretase and γ-secretase to yield Aβ, MT5-MMP η-secretase activity can be considered proamyloidogenic (Afram et al, 2023).…”

“…Processing of CTF-η by ADAM10/17 and BACE1 releases Aη-α and Aη-β (Figure 1) (Afram et al, 2023;Willem et al, 2015). Aη-α and Aη-β are synaptotoxic (García-González et al, 2019;Mensch et al, 2021;Willem et al, 2015). CTF-η by can also be a precursor to Aβ generation (Afram et al, 2023).…”