Synapse Formation and Function Is Modulated by the Amyloid Precursor Protein

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-receptormediated 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.

γ-Secretase Inhibition Reduces Spine DensityIn Vivovia an Amyloid Precursor Protein-Dependent Pathway

“…The enhanced spine density in the cerebral cortex of APP KO mice supports previous in vitro findings showing that cultured hippocampal neurons from newborn mice as well as hippocampal sections from adult APP KO mice exhibit an increased number of synaptic endings (Priller et al, 2006). Detailed patch-clamp studies in autaptic hippocampal neurons further revealed that a lack of APP increases the number of synapses but does not affect the function of individual excitatory synapses either presynaptically or postsynaptically (Priller et al, 2006).…”

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

“…This short peptide is a protein segment located in the transmembrane domain of APP that is an integral membrane protein that attaches to biological membranes 16. This segment consists of seven hydrophobic residues and three hydrophilic residues ( Figure 1 a), where the hydrophobic residues make up the majority of the segment.…”

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

“…Since cPLA 2 modifies the transport of several proteins between Golgi vesicles and plasma membranes in nonneuronal cells as we discussed above (Choukroun et al, 2000;Regan-Klapisz et al, 2009), cPLA 2 might regulate APP trafficking and metabolism similar to other synaptic proteins into various lipid compartments. Besides its role in A␤ peptide generation, APP protein is required for synaptic plasticity and other neuronal functions (Dawson et al, 1999;Priller et al, 2006). Moreover A␤ oligomers bind to the cognate A␤ extracellular domain of APP and generate a G protein-dependent intracellular signaling pathway through APP dimerization (Shaked et al, 2006(Shaked et al, , 2009.…”