Unravelling the contribution of the APP-derived peptide AETA in Alzheimer’s disease pathology

The amyloid-β precursor protein (APP), physiologically cleaved, allows the secretion of Amyloid-β (Aβ) but also of other peptides, including the peptides secreted from the η-secretase pathway (AETA peptides) that we described previously (Willem et al., Nature 2015, PMID:26322584). We now obtained reliable data showing that AETA controls both ionotropic and non-ionotropic signalling of NMDA receptors (NMDAr) (Dunot et al, in revision). Here we asked whether AETA, due to its new-found role as a modulator of NMDArs, could be implicated in Alzheimer’s disease (AD) aetiology. First, we quantified AETA levels in human prefrontal cortex and hippocampi of control and AD patients and observed that AETA accumulates in AD brains. To understand how this might perturb brain information processing, we generated a new mouse model, the AETA-m line, which harbours a chronic increase of the secreted human form of AETA in the brain. Behaviourally, these mice exhibit altered anxiety, social interaction behaviour and long-term spatial memory. These perturbations correlate with alterations of the NMDAr activity and NMDAr-dependent synaptic plasticity. Hippocampal neurons of AETA-m also exhibit lower spine density. As other hallmarks of AD-like pathology, we observed modifications in markers of astrocyte and microglia activity. Finally, an RNAseq was performed on hippocampi of these mice to seek out other functional alterations. We observed a downregulation of genes related to excitatory synapse signalling and an upregulation of genes related to the extracellular matrix. All together, these results identify AETA as a new contributor to several pathological features pertaining to AD.