Oddo Salvatore, Caccamo Antonella, Cheng David, LaFerla Frank M
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697-4545, USA.
Brain Pathol. 2009 Jul;19(3):421-30. doi: 10.1111/j.1750-3639.2008.00194.x. Epub 2008 Jul 24.
The inheritance of the epsilon4 allele of the apolipoprotein E (apoE) gene is the major genetic risk factor for developing late-onset Alzheimer disease. In transgenic mice overexpressing amyloid precursor protein (APP), replacing the endogenous mouse apoE gene with the human apolipoprotein E4 (apoE4) gene alters the distribution of amyloid-beta (Abeta) deposits from the brain parenchyma to the vasculature. However, the effects of this distribution on the onset and progression of tau pathology remain to be established. To address this issue, we used a genetic approach to replace the endogenous apoE gene with the human apoE4 allele in the 3xTg-AD mice. We showed that changing Abeta distribution from the parenchyma to the vasculature drastically reduces the tau pathology. The 3xTg-AD mice expressing the human apoE4 gene were virtually depleted of any somatodendritic tau deposits. These data strongly suggest that the somatodendritic tau accumulation is dependent on the parenchyma Abeta deposits.
载脂蛋白E（apoE）基因的ε4等位基因的遗传是晚发性阿尔茨海默病发生的主要遗传风险因素。在过表达淀粉样前体蛋白（APP）的转基因小鼠中，用人载脂蛋白E4（apoE4）基因替代内源性小鼠apoE基因会使淀粉样β（Aβ）沉积物的分布从脑实质改变为脉管系统。然而，这种分布对tau病理发生和进展的影响仍有待确定。为了解决这个问题，我们采用遗传学方法在3xTg-AD小鼠中用人apoE4等位基因替代内源性apoE基因。我们发现，将Aβ分布从实质改变为脉管系统可显著减少tau病理。表达人apoE4基因的3xTg-AD小鼠几乎没有任何树突体tau沉积物。这些数据有力地表明，树突体tau积累依赖于实质Aβ沉积物。
