Aβ oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms
Aβ oligomer-mediated long-term potentiation impairment involves protein phosphatase 1-dependent mechanisms
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DOI：
10.1523/jneurosci.0395-07.2007
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发表时间：
2007-07-18
影响因子：
5.3
通讯作者：
Mansuy, Isabelle M.
中科院分区：
文献类型：
--
作者：
Knobloch, Marlen;Farinelli, Melissa;Mansuy, Isabelle M.
淀粉样β（A β）寡聚体来源于淀粉样前体蛋白（APP）的蛋白水解裂解，可在体内和体外损害记忆和海马长时程增强（LTP）。它们被认为是阿尔茨海默病中的主要神经毒性剂。这种毒性对突触功能的潜在机制是复杂的，尚未完全理解。在这里，我们提供了第一个证据，这些机制涉及蛋白磷酸酶1（PP1）。使用一种新的转基因小鼠模型，表达人类APP与瑞典和北极突变，使A β更容易形成寡聚体（arcA β小鼠），我们表明，LTP损伤诱导的A β寡聚体可以完全逆转的PP1抑制在体外。我们进一步证明，内源性PP1在体内的遗传抑制赋予抵抗A β寡聚体介导的毒性和保护LTP。总体而言，这些结果表明，PP1是AD病理机制中的关键参与者。
Amyloid beta (A beta) oligomers are derived from proteolytic cleavage of amyloid precursor protein (APP) and can impair memory and hippocampal long-term potentiation (LTP) in vivo and in vitro. They are recognized as the primary neurotoxic agents in Alzheimer's disease. The mechanisms underlying such toxicity on synaptic functions are complex and not fully understood. Here, we provide the first evidence that these mechanisms involve protein phosphatase 1 (PP1). Using a novel transgenic mouse model expressing human APP with the Swedish and Arctic mutations that render A beta more prone to form oligomers (arcA beta mice), we show that the LTP impairment induced by A beta oligomers can be fully reversed by PP1 inhibition in vitro. We further demonstrate that the genetic inhibition of endogenous PP1 in vivo confers resistance to A beta oligomer-mediated toxicity and preserves LTP. Overall, these results reveal that PP1 is a key player in the mechanisms of AD pathology.