Noradrenaline deficiency in brain increases β-amyloid plaque burden in an animal model of Alzheimer's disease
Noradrenaline deficiency in brain increases β-amyloid plaque burden in an animal model of Alzheimer's disease
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DOI：
10.1016/j.neurobiolaging.2006.06.003
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发表时间：
2007-08-01
影响因子：
4.2
通讯作者：
Feinstein, Douglas L.
中科院分区：
文献类型：
--
作者：
Kalinin, Sergey;Gavrilyuk, Vitaliy;Feinstein, Douglas L.
蓝斑（LC）去甲肾上腺素能（NA）神经元的损失发生在包括阿尔茨海默病（AD）的几种神经退行性疾病中。体外和体内研究表明，NA影响AD疾病的几个特征，包括炎症、神经变性和认知功能。在目前的研究中，我们测试了LC损失是否影响β淀粉样蛋白（A β）斑块沉积。通过用选择性神经毒素N-（2-氯乙基）-N-乙基-2-溴苄胺DSP 4（从3月龄开始每2周5 mg/kg）处理表达突变V717 F人淀粉样前体蛋白（APP）的转基因小鼠，诱导LC神经元变性。在9月龄时，当对照小鼠显示低淀粉样蛋白负荷时，DSP 4处理的小鼠显示A β斑块的平均数量增加约5倍。这伴随着APP C-末端切割片段水平的增加。DSP 4处理增加小胶质细胞和星形胶质细胞活化。在体内，DSP 4处理降低了A β降解酶脑啡肽酶的表达和活性，而在体外NA增加了小胶质细胞对A β 1-42的吞噬作用。这些结果表明，需要从LC去甲肾上腺素能神经支配，以保持足够的A β清除，因此，LC变性可能有助于AD的发病机制。(c)2006年爱思唯尔公司All rights reserved.
Loss of Locus coeruleus (LC) noradrenergic (NA) neurons occurs in several neurodegenerative conditions including Alzheimer's disease (AD). In vitro and in vivo studies have shown that NA influences several features of AD disease including inflammation, neurodegeneration, and cognitive function. In the current study we tested if LC loss influenced beta amyloid (A beta) plaque deposition. LC neuronal degeneration was induced in transgenic mice expressing mutant V717F human amyloid precursor protein (APP) by treatment with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine DSP4 (5 mg/kg every 2 weeks beginning at age 3 months). At 9 months of age, when control mice show low amyloid load, DSP4-treated mice showed an approximately 5-fold increase in the average number of A beta plaques. This was accompanied by an increase in the levels of APP C-terminal cleavage fragments. DSP4-treatment increased both microglial and astroglial activation. In vivo, DSP4-treatment decreased expression and activity of the A beta degrading enzyme neprilysin, while in vitro NA increased phagocytosis of A beta 1-42 by microglia. These findings suggest that noradrenergic innervation from LC are needed to maintain adequate A beta clearance, and therefore that LC degeneration could contribute to AD pathogenesis. (c) 2006 Elsevier Inc. All rights reserved.