Physiological APP processing is required for synaptic plasticity and cognition

While the accumulation of Aβ peptides, derived by proteolytic cleavage from the amyloid precursor protein APP, constitutes a hallmark of Alzheimer's disease, the question of whether endogenous, physiological APP processing serves an essential role for normal brain function(s) has remained elusive. Here, we modified the mouse APP locus to delete the endogenous α- and β-secretase sites (APP residues S592-G621) while preserving the transmembrane topology and the APP C-terminus. These novel knockin mice (termed APPΔS622) lack APPsα, APPβ, and Aβ production and show only minimal soluble APPs shedding. These APPΔS622 mice provide a unique model to distinguish between functions mediated by unprocessed cell surface APP involved in synaptic adhesion or by proteolytic fragments. Strikingly, APPΔS622 mice exhibit pronounced impairments in both long-term potentiation (LTP) and homeostatic forms of synaptic plasticity. Extracellular field recordings revealed significant deficits in hippocampal LTP, associated with a reduced density of mature spines and reduced spine head size. LTP deficits could be restored by APPsα application, suggesting a requirement for non-amyloidogenic APP processing for LTP. In addition, APPΔS622 mice lacking endogenous Aβ displayed a lack of homeostatic synaptic scaling in response to network impairment that could be specifically rescued by exogenous Aβ. Importantly, these deficits in different forms of synaptic plasticity also led to impairments in cognitive behavior. In summary, our findings reveal an essential role of physiological APP processing products to differentially regulate complementary forms of synaptic plasticity that are critical for network stability, normal brain function and cognition.