The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.

The amyloid precursor protein family (APP/APLPs) has essential roles for neuromuscular synapse development and for the formation and plasticity of synapses within the CNS. Despite this, it has remained unclear whether APP mediates its functions primarily as a cell surface adhesion and signaling molecule or via its numerous proteolytic cleavage products. To address these questions, we followed a genetic approach and used APPΔCT15 knockin mice lacking the last 15 amino acids of APP, including the highly conserved YENPTY protein interaction motif. To circumvent functional compensation by the closely related APLP2, these mice were bred to an APLP2-KO background to generate APPΔCT15-DM double mutants. These APPΔCT15-DM mice were partially viable and displayed defects in neuromuscular synapse morphology and function with impairments in the ability to sustain transmitter release that resulted in muscular weakness. In the CNS, we demonstrate pronounced synaptic deficits including impairments in LTP that were associated with deficits in spatial learning and memory. Thus, the APP-CT15 domain provides essential physiological functions, likely via recruitment of specific interactors. Together with the well-established role of APPsα for synaptic plasticity, this shows that multiple domains of APP, including the conserved C-terminus, mediate signals required for normal PNS and CNS physiology. In addition, we demonstrate that lack of the APP-CT15 domain strongly impairs Aβ generation in vivo, establishing the APP C-terminus as a target for Aβ-lowering strategies. SIGNIFICANCE STATEMENT: Synaptic dysfunction and cognitive decline are early hallmark features of Alzheimer's disease. Thus, it is essential to elucidate the in vivo function(s) of APP at the synapse. At present, it is unknown whether APP family proteins function as cell surface receptors, or mainly via shedding of their secreted ectodomains, such as neurotrophic APPsα. Here, to dissect APP functional domains, we used APP mutant mice lacking the last 15 amino acids that were crossed onto an APLP2-KO background. These APPΔCT15-DM mice showed defects in neuromuscular morphology and function. Synaptic deficits in the CNS included impairments of synaptic plasticity, spatial learning, and memory. Collectively, this indicates that multiple APP domains, including the C-terminus, are required for normal nervous system function.