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Experimental Genetics Group
J Biol Chem. 2007 Jan 12;282(2):1119-27. Priller C1, Dewachter I2, Vassallo N3, Paluch S1, Pace C1, Kretzschmar HA1, Van Leuven F2, Herms J1*. 1Department of Neuropathology, Ludwig-Maximilians-Unversität Munich, München, Germany. 2Experimental Genetics Group, K.U.Leuven, Leuven, Belgium. 3Department of Physiology and Biochemistry, University of Malta, Msida, Malta. *Corresponding author. 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. Both alterations could be rescued by the application of a gamma-secretase blocker. On the other hand, the application of synthetic soluble Abeta42 in wild-type neurons induced the PS1 mutant phenotype on synaptic strength. Together, these findings strongly suggest that the expression of mutant PS1 in cultured neurons depresses synaptic transmission by causing a physical reduction in the number of synapses. This hypothesis is consistent with morphometic and semiquantitative immunohistochemical analysis, revealing a decrease in synaptophysin-positive puncta in PS1 mutant hippocampal neurons.  FULL TEXT |
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