Topic: amyloid-β precursor protein

The amyloid-β precursor protein (APP) is a transmembrane protein constitutively expressed in the brain and highly implicated in Alzheimer’s disease aetiology. We previously identified a novel cleavage site of APP, the η-secretase site (Willem et al. Nature 2015, PMID:26322584). Peptides resulting from this cleavage and α- or β-secretase-dependent proteolysis are the extracellular soluble AETA peptides (Aη-α or Aη-β, respectively). Our previous work also demonstrated that AETA modulates synaptic plasticity and significantly reduces calcium activity in the hippocampus (HPC) in vivo. These result

NMDA receptors (NMDARs) are ionotropic receptors crucial for brain information processing. Yet, evidence also supports an ion flux-independent signaling mode mediating synaptic long-term depression (LTD) and spine shrinkage. How these different modes of NMDAR activity are controlled remains unknown. Here, we identify AETA (Aη), an amyloid-β precursor protein (APP) cleavage product, as an NMDAR modulator with the unique dual regulatory capacity to impact both signaling modes. AETA inhibits ionotropic NMDAR activity, principally of GluN2A containing heteromers, by competing with the co-agonist a