Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer's disease
Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer's disease
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DOI：
10.1523/jneurosci.0297-04.2004
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发表时间：
2004-03-31
影响因子：
5.3
通讯作者：
Bush, AI
中科院分区：
文献类型：
--
作者：
Friedlich, AL;Lee, JY;Bush, AI
脑淀粉样血管病（CAA）在阿尔茨海默病（AD）中很常见，并可能导致痴呆和脑出血。实质β-淀粉样蛋白沉积依赖于锌转运蛋白3（ZnT 3）的活性，锌转运蛋白3是一种新皮质突触囊泡膜蛋白，其导致囊泡中可交换的Zn 2+的富集，其在神经传递上被外化。然而，锌对血管β-淀粉样蛋白沉积的贡献仍不清楚。在这里，我们确定了第一次在正常小鼠的脑血管壁的可交换池的锌2+。在AD转基因小鼠模型（Tg 2576）中，这种组织化学反应性Zn 2+富集于CAA中，并且在这些小鼠中，在Znt 3基因的靶向破坏后，CAA发生急剧减少。此外，在Znt 3基因敲除小鼠中，血管周围间隙中可交换的Zn 2 + [通过N-（6-甲氧基-8-喹啉基）-对-羧基苯甲酰基磺酰胺（TFL-Zn）检测]的量在新皮质中显着减少，但在外周器官中却没有。在野生型小鼠的脑血管壁或血液成分中未检测到ZnT 3。因此，突触ZnT 3活性可能通过间接提高脑血管周围空间中可交换的Zn 2+浓度来促进CAA。
Cerebral amyloid angiopathy (CAA) is common in Alzheimer's disease ( AD) and may contribute to dementia and cerebral hemorrhage. Parenchymal beta-amyloid deposition is dependent on the activity of zinc transporter 3 (ZnT3), a neocortical synaptic vesicle membrane protein that causes enrichment of exchangeable Zn2+ in the vesicle, which is externalized on neurotransmission. However, the contribution of zinc to vascular beta-amyloid deposition remains unclear. Here, we identify for the first time an exchangeable pool of Zn2+ in the cerebrovascular wall of normal mice. This histochemically reactive Zn2+ is enriched in CAA in a transgenic mouse model of AD (Tg2576), and a dramatic reduction of CAA occurs after targeted disruption of the Znt3 gene in these mice. Also, in Znt3 knock-out mice, the amount of exchangeable Zn2+ [detected by N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulphonamide (TFL-Zn)] in the perivascular space was significantly decreased in the neocortex but not in peripheral organs. ZnT3 was not detected in the cerebral vessel walls or in blood components of wild-type mice. Thus, synaptic ZnT3 activity may promote CAA by indirectly raising exchangeable Zn2+ concentrations in the perivascular spaces of the brain.