Evidence That Synaptically Released β-Amyloid Accumulates as Extracellular Deposits in the Hippocampus of Transgenic Mice
Evidence That Synaptically Released β-Amyloid Accumulates as Extracellular Deposits in the Hippocampus of Transgenic Mice
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DOI：
10.1523/jneurosci.22-22-09785.2002
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发表时间：
2002-11
期刊：
影响因子：
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通讯作者：
Orly Lazarov;Michael K. Lee;D. Peterson;S. Sisodia
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文献类型：
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作者：
Orly Lazarov;Michael K. Lee;D. Peterson;S. Sisodia
阿尔茨海默病的一个神经病理学特征是淀粉样蛋白(Aβ，Aβ)多肽在海马区和大脑皮层的老年斑中沉积。β来源于更大的完整膜蛋白，称为淀粉样前体蛋白(APP)。我们先前证明，由内嗅皮层神经元合成的APP通过穿支通路运输到齿状回的突触前终末。我们报道，尽管全长APP和膜拴系的C-末端APP衍生物(APP-CTF)积累在终端区，但这些位点产生的Aβ肽是不确定的。为了验证这样一种假设，即从轴向运输的APP产生的APP-CTF进一步代谢成Aβ肽，随后释放并沉积在神经末梢近端，我们对转基因小鼠的穿孔通路进行了单侧刀状损伤，显示出海马淀粉样蛋白沉积。我们观察到同侧齿状回的淀粉样蛋白负荷显著减少，这一发现使我们得出结论，轴向运输的APP产生Aβ肽，这些肽从齿状回的突触前部位释放并沉积在细胞外斑块中。此外，我们的发现与以下观点是一致的，即Aβ沉积是动态结构，穿通径损毁改变了Aβ产生-沉积到清除之间的平衡，这是由于APP从内嗅皮层到海马区终末区域的轴突运输受阻所致。
A neuropathological hallmark of Alzheimer's disease is the deposition of amyloid-β (Aβ) peptides in senile plaques in the hippocampus and cerebral cortex. Aβ is derived from larger integral membrane proteins termed amyloid precursor proteins (APP). We demonstrated previously that APP, synthesized by neurons in the entorhinal cortex, is transported via the perforant pathway to presynaptic terminals in the dentate gyrus. We reported that, although full-length APP and membrane-tethered, C-terminal APP derivatives (APP-CTFs) accumulate at terminal fields, the production of Aβ peptides at these sites was indeterminate. To test the hypothesis that APP-CTFs, generated from axonally transported APP, are further metabolized to Aβ peptides that are subsequently released and deposited proximal to nerve terminals, we created unilateral knife lesions of the perforant pathway of transgenic mice that exhibit hippocampal amyloid deposits. We observed pronounced reductions in amyloid burden in the ipsilateral dentate gyrus, findings that lead us to conclude that axonally transported APP gives rise to Aβ peptides that are released from presynaptic sites in the dentate gyrus and deposited in extracellular plaques. Moreover, our findings are consistent with the view that Aβ deposits are dynamic structures and that the perforant path lesion alters the equilibrium between Aβ production–deposition toward clearance as a consequence of blocked axonal transport of APP from the entorhinal cortex to terminal fields in the hippocampus.