β-amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or β-amyloid deposits
β-amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or β-amyloid deposits
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DOI：
10.1073/pnas.0602896103
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发表时间：
2006-06-06
影响因子：
11.1
通讯作者：
Koistinaho, Jari
中科院分区：
文献类型：
--
作者：
Malm, Tarja;Ortt, Michael;Koistinaho, Jari
β-淀粉样蛋白（A β）多肽在阿尔茨海默病（AD）的发病机制中起关键作用，其特征在于认知功能的进行性下降、A β沉积和神经元缠结的形成以及神经元的丢失。在动物模型中，A β的基因产生增加或直接脑内给药导致A β沉积、神经胶质增生和认知功能受损。衰老是否会使大脑容易产生A β，以及A β诱导的学习障碍是否需要炎症，目前尚不清楚。我们发现，脑室内注射A β（1 - 42）导致9个月大的小鼠出现学习障碍，而2.5个月大的小鼠则没有。输注后12周可检测到的缺陷与Cu，Zn超氧化物歧化酶活性的轻微降低相关，但与A β沉积无关，也与神经胶质增生无关。在大鼠中，A β输注诱导了输注后6个月可检测到的学习缺陷。大鼠中约20%的A β免疫反应性与星形胶质细胞相关。动物脑脊液的NMR光谱分析显示，在All输注的大鼠中，几种代谢物（包括乳酸盐和肌醇）有强烈的减少趋势，支持功能失调的星形胶质细胞的观点。即使是脑A β（1 - 42）浓度的轻微增加也可能破坏星形胶质细胞的正常代谢，导致神经元功能改变和与年龄相关的学习缺陷发展，而与A β沉积和炎症无关。
beta-Amyloid (A beta) polypeptide plays a critical role in the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of A beta deposits and neurofibrillary tangles, and loss of neurons. Increased genetic production or direct intracerebral administration of A beta in animal models results in A beta deposition, gliosis, and impaired cognitive functions. Whether aging renders the brain prone to A beta and whether inflammation is required for A beta-induced learning deficits is unclear. We show that intraventricular infusion of A beta(1-42) results in learning deficits in 9-month-old but not 2.5-month-old mice. Deficits that become detectable 12 weeks after the infusion are associated with a slight reduction in Cu,Zn superoxide dismutase activity but do not correlate with A beta deposition and are not associated with gliosis. In rats, A beta infusion induced learning deficits that were detectable 6 months after the infusion. Approximately 20% of the A beta immunoreactivity in rats was associated with astrocytes. NMR spectrum analysis of the animals cerebrospinal fluid revealed a strong reduction trend in several metabolites in All-infused rats, including lactate and myo-inositol, supporting the idea of dysfunctional astrocytes. Even a subtle increase in brain A beta(1-42) concentration may disrupt normal metabolism of astrocytes, resulting in altered neuronal functions and age-related development of learning deficits independent of A beta deposition and inflammation.