期刊
NEUROBIOLOGY OF AGING
卷 29, 期 5, 页码 639-652出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2006.11.019
关键词
presenilin; FAD mutation; synaptic plasticity; NMDA receptor; synaptic vesicles; presynaptic; postsynaptic; tau
The function of presenilin1 (PS1) in intra-membrane proteolysis is undisputed, as is its role in neurodegeneration in FAD, in contrast to its exact function in normal conditions. In this study, we analyzed synaptic plasticity and its underlying mechanisms biochemically in brain of mice with a neuron-specific deficiency in PS1 (PS1 (n-/-)) and compared them to mice that expressed human mutant PS1 [A246E] or wild-type PS1. PS1 (n-/-) mice displayed a subtle impairment in Schaffer collateral hippocampal long-term potentiation (LTP) as opposed to normal LTP in wild-type PS1 mice, and a facilitated LTP in mutant PS1 [A246E] mice. This finding correlated with, respectively, increased and reduced NMDA receptor responses in PSI [A246E] mice and PS1 (n-/-) mice in hippocampal slices. Postsynaptically, levels of NRI/NR2B NMDA-receptor subunits and activated alpha-CaMKII were reduced in PSI(n-/-) mice, while increased in PS1[A246E] mice. In addition, PS1(n-/-) mice, displayed reduced paired pulse facilitation, increased synaptic fatigue and lower number of total and docked synaptic vesicles, implying a presynaptic function for wild-type presenilin1, unaffected by the mutation in PS1[A246E] mice. In contrast to the deficiency in PS1, mutant PS1 activated GSK-3 beta by decreasing phosphorylation on Ser-9, which correlated with increased phosphorylation of protein tau at Ser-396-Ser-404 (PHF1/AD2 epitope). The synaptic functions of PS1, exerted on presynaptic vesicles and on postsynaptic NMDA-receptor activity, were concluded to be independent of alterations in GSK-3 beta activity and phosphorylation of protein tau. (c) 2006 Elsevier Inc. All rights reserved.
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