Synapse Formation and Function Is Modulated by the Amyloid Precursor Protein

TLDR

The amyloid precursor protein (APP) is implicated in Alzheimer’s disease, yet its normal neuronal function at synapses remains unclear. The authors used autaptic hippocampal neuron cultures to measure evoked AMPA‑ and NMDA‑receptor‑mediated EPSCs in APP‑knockout neurons. APP deficiency in hippocampal neurons leads to larger evoked EPSCs, an expanded readily releasable vesicle pool, higher spontaneous release frequency, and increased synaptophysin puncta, indicating more functional synapses.

Abstract

The amyloid precursor protein (APP) is critical in the pathogenesis of Alzheimer's disease. The question of its normal biological function in neurons, in which it is predominantly located at synapses, is still unclear. Using autaptic cultures of hippocampal neurons, we demonstrate that hippocampal neurons lacking APP show significantly enhanced amplitudes of evoked AMPA- and NMDA-receptor-mediated EPSCs. The size of the readily releasable synaptic vesicle pool was also increased in neurons lacking APP, whereas the release probability was not affected. In addition, the analysis of spontaneous miniature synaptic currents revealed an augmented frequency in neurons lacking APP, whereas the amplitude of miniature synaptic currents was not found to be altered. Together, these findings strongly indicate that lack of APP increases the number of functional synapses. This hypothesis is further supported by morphometric immunohistochemical analysis revealing an increase of synaptophysin-positive puncta per cultured APP knock-out neuron. In conclusion, lack of APP affects synapse formation and transmission in cultured hippocampal neurons.