Buttini Manuel, Yu Gui-Qiu, Shockley Kristina, Huang Yadong, Jones Brian, Masliah Eliezer, Mallory Margaret, Yeo Tracy, Longo Frank M, Mucke Lennart
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94141-9100, USA.
J Neurosci. 2002 Dec 15;22(24):10539-48. doi: 10.1523/JNEUROSCI.22-24-10539.2002.
The most frequent human apolipoprotein (apo) E isoforms, E3 and E4, differentially affect Alzheimer's disease (AD) risk (E4 > E3) and age of onset (E4 < E3). Compared with apoE3, apoE4 promotes the cerebral deposition of amyloid beta (Abeta) peptides, which are derived from the amyloid precursor protein (APP) and play a central role in AD. However, it is uncertain whether Abeta deposition into plaques is the main mechanism by which apoE isoforms affect AD. We analyzed murine apoE-deficient transgenic mice expressing in their brains human APP (hAPP) and Abeta together with apoE3 or apoE4. Because cognitive decline in AD correlates better with decreases in synaptophysin-immunoreactive presynaptic terminals, choline acetyltransferase (ChAT) activity, and ChAT-positive fibers than with plaque load, we compared these parameters in hAPP/apoE3 and hAPP/apoE4 mice and singly transgenic controls at 6-7, 12-15, and 19-24 months of age. Brain aging in the context of high levels of nondeposited human Abeta resulted in progressive synaptic/cholinergic deficits. ApoE3 delayed the synaptic deficits until old age, whereas apoE4 was not protective at any of the ages analyzed. Old hAPP/apoE4 mice had more plaques than old hAPP/apoE3 mice, but synaptic/cholinergic deficits preceded plaque formation in hAPP/apoE4 mice. Moreover, despite their different plaque loads, old hAPP/apoE4 and hAPP/apoE3 mice had comparable synaptic/cholinergic deficits, and these deficits were found not only in the hippocampus but also in the neocortex, which in most mice contained no plaques. Thus, apoE3, but not apoE4, delays age- and Abeta-dependent synaptic deficits through a plaque-independent mechanism. This difference could contribute to the differential effects of apoE isoforms on the risk and onset of AD.
人类最常见的载脂蛋白（apo）E亚型E3和E4对阿尔茨海默病（AD）风险（E4>E3）和发病年龄（E4<E3）有不同影响。与apoE3相比，apoE4促进淀粉样β（Aβ）肽在大脑中的沉积，Aβ肽由淀粉样前体蛋白（APP）衍生而来，在AD中起核心作用。然而，Aβ沉积形成斑块是否是apoE亚型影响AD的主要机制尚不确定。我们分析了在大脑中共同表达人类APP（hAPP）、Aβ以及apoE3或apoE4的小鼠apoE基因缺陷转基因小鼠。由于AD中的认知衰退与突触素免疫反应性突触前终末、胆碱乙酰转移酶（ChAT）活性和ChAT阳性纤维的减少相关性更好，而不是与斑块负荷相关性更好，因此我们比较了6 - 7个月、12 - 15个月和19 - 24个月龄的hAPP/apoE3和hAPP/apoE4小鼠以及单转基因对照小鼠的这些参数。在高水平未沉积的人类Aβ背景下的大脑老化导致了渐进性的突触/胆碱能缺陷。apoE3将突触缺陷延迟至老年，而apoE4在任何分析的年龄都没有保护作用。老年hAPP/apoE4小鼠比老年hAPP/apoE3小鼠有更多斑块，但在hAPP/apoE4小鼠中，突触/胆碱能缺陷先于斑块形成。此外尽管老年hAPP/apoE4和hAPP/apoE3小鼠的斑块负荷不同，但它们有相当的突触/胆碱能缺陷，并且这些缺陷不仅在海马体中发现，还在大多数小鼠没有斑块的新皮层中发现。因此，apoE3而非apoE4通过不依赖斑块的机制延迟年龄和Aβ依赖的突触缺陷。这种差异可能导致apoE亚型对AD风险和发病的不同影响。
