Facchinetti Patricia, Dorard Emilie, Contremoulins Vincent, Gaillard Marie-Claude, Déglon Nicole, Sazdovitch Véronique, Guihenneuc-Jouyaux Chantal, Brouillet Emmanuel, Duyckaerts Charles, Allinquant Bernadette
INSERM UMR 894, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
ImagoSeine, Institut Jacques Monod, UMR 7592, CNRS and Université Paris Diderot, Paris, France.
Neurobiol Aging. 2014 May;35(5):958-68. doi: 10.1016/j.neurobiolaging.2013.08.039. Epub 2013 Nov 5.
Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.
在阿尔茨海默病（AD）患者大脑中，半胱天冬酶切割的淀粉样前体蛋白（APPcc）和SET增加并在神经元细胞质中错误定位。易位至细胞质的SET可诱导tau蛋白过度磷酸化。为阐明错误定位的APPcc与SET之间的假定关系，我们研究了5名对照者、3名唐氏综合征患者和10名阿尔茨海默病患者海马体中它们的水平和分布。在唐氏综合征患者和阿尔茨海默病患者中，CA1区的APPcc和SET水平升高，且二者在神经元细胞质中的定位频率在CA1区较高，在CA4区较低。由于APPcc的增加在AD早期就已出现，我们用慢病毒构建体在成年小鼠的CA1区和齿状回神经元中过表达APPcc。CA1区而非齿状回中APPcc的过表达诱导了内源性SET易位和tau蛋白过度磷酸化。这些数据表明，CA1神经元中APPcc的增加可能是导致SET易位以及AD通过tau蛋白过度磷酸化进展的早期事件。
