Aims

Physiopathological cleavage of the amyloid precursor protein (APP) allows the secretion of Aβ but also of other peptides, including peptides secreted from the η-secretase pathway, named Aη peptides, described in Willem et al., Nature, 2015. These Aη peptides acutely impair neuron function even at low nanomolar concentrations (Mensch et al. Alzheimers Res Ther., 2021). Here we analysed the consequences of chronic in vivo alterations of Aη peptide levels on hippocampal function.

Methods

To modulate Ah levels in vivo, two new mouse models were created. The first model, named MISEPA2, harbours a transgene expressing a secreted from of Aη-α allowing for a chronic increase of human Aη-α levels in the brain. The second model, named APPΔη, harbours a deletion of a portion of endogenous APP that prevents η-secretase processing. We characterized these models by analysing APP peptides levels by immunoblotting, analysing synaptic plasticity by electrophysiology and analysing spatial memory by submitting the mice to the Morris water maze.

Results

MISEPA2 mice exhibit normal levels of Aβ in the hippocampus. Long-term potentiation (LTP), long-term depression (LTD) and spatial memory are altered in these mice.

APPΔη mice exhibit normal levels of Aβ in the hippocampus. LTP is normal, but LTD is absent and rescued upon acute application of synthetic Aη-α peptide. Spatial memory is impaired in these mice.

Conclusions

These results show that a chronic increase of Aη-α is detrimental to hippocampal function. We also validate the hypothesis that the peptides secreted from the η-secretase pathway are necessary for endogenous modulation of synaptic communication and memory processing.