Excitatory synaptic transmission is depressed in cultured hippocampal neurons of APP/PS1 mice.

One of the strongest anatomical correlates of the degree of clinical impairment in Alzheimer's disease is a decrease in synaptic density. A detailed understanding of the pathophysiological mechanism operating at a synaptic level remains incomplete, in particular whether the pre- or the post-synaptic compartment is initially involved. Here, we studied synaptic transmission in autaptic hippocampal cultures from a double-transgenic mouse model (APPPS1, APP(swe) and PS1(L166P)) and a single-mutant APP transgenic model (APP23, APPswe).

Mutant presenilin 1 alters synaptic transmission in cultured hippocampal neurons.

Mutations in presenilins are the major cause of familial Alzheimer disease, but the precise pathogenic mechanism by which presenilin (PS) mutations cause synaptic dysfunction leading to memory loss and neurodegeneration remains unclear. Using autaptic hippocampal cultures from transgenic mice expressing human PS1 with the A246E mutation, we demonstrate that mutant PS1 significantly depressed the amplitude of evoked alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptor-mediated synaptic currents. Analysis of the spontaneous miniature synaptic activity revealed a lower frequency of miniature currents but normal miniature amplitude.

Synapse formation and function is modulated by the amyloid precursor protein.

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.