INFLAMMATORY PROCESSES INDUCE BETA-AMYLOID PRECURSOR PROTEIN-CHANGES IN MOUSE-BRAIN
INFLAMMATORY PROCESSES INDUCE BETA-AMYLOID PRECURSOR PROTEIN-CHANGES IN MOUSE-BRAIN
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DOI：
10.1073/pnas.92.7.3032
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发表时间：
1995-03-28
影响因子：
11.1
通讯作者：
MARIANI, J
中科院分区：
文献类型：
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作者：
BRUGG, B;DUBREUIL, YL;MARIANI, J
在阿尔茨海默病中，遗传易感性和环境因素的组合可能导致β-淀粉样前体蛋白（APP）表达、β-淀粉样肽沉积和神经元损失的变化。诸如头部损伤或急性感染等触发炎症过程的因素可能在疾病的发展中起关键作用。在目前的体内研究中，我们发现，在小鼠大脑中，外周刺激脂多糖（LPS）诱导的炎性细胞因子mRNA（白细胞介素1 β和白细胞介素6）的瞬时增加，随后在小脑中的APP亚型的表达的变化，但不是在大脑皮层。这些变化包括APP-695的减少和Kunitz蛋白酶催化剂携带亚型（KPI-APP）的增加。在小脑的staggerer小鼠突变，浦肯野细胞和颗粒细胞的严重损失发生，这些白细胞介素的基础mRNA水平升高，并增加在KPI-APP/APP-695的比例相比，野生型小鼠进行了观察。LPS刺激进一步加重了这些异常。这项研究表明，急性和慢性炎症过程中起着重要的作用，APP表达的变化可能与神经退行性变。
In Alzheimer disease, a combination of genetic predisposition and environmental factors may contribute to changes in beta-amyloid precursor protein (APP) expression, beta-amyloid peptide deposition, and neuronal loss. Factors such as head injury or acute infection that trigger inflammatory processes may play a crucial role in development of the disease. In the present in vivo study, we showed that, in mouse brain, peripheral stimulation with lipopolysaccharide (LPS) induced a transient increase in the inflammatory cytokine mRNAs (interleukin 1 beta and interleukin 6), followed by changes in expression of APP isoforms in the cerebellum but not in the cerebral cortex. These changes consisted of a decrease in the APP-695 and an increase in the Kunitz protease inhibitor-bearing isoforms (KPI-APP). In the cerebellum of the staggerer mouse mutant, where a severe loss of Purkinje and granule cells occurs, basal mRNA levels of these interleukins were elevated and an increase in the KPI-APP/APP-695 ratio compared to wild-type mice was observed. These abnormalities were further accentuated by LPS stimulation. This study shows that acute and chronic inflammatory processes play an important role in changes in APP expression possibly associated with neurodegeneration.