Increased Inflammatory Response Both in Brain and in Periphery in Presenilin 1 and Presenilin 2 Conditional Double Knock-Out Mice
Increased Inflammatory Response Both in Brain and in Periphery in Presenilin 1 and Presenilin 2 Conditional Double Knock-Out Mice
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DOI：
10.3233/jad-2009-1164
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发表时间：
2009-01-01
影响因子：
4
通讯作者：
Mei, Bing
中科院分区：
文献类型：
--
作者：
Jiang, Xu;Zhang, Dongli;Mei, Bing
据报道，小鼠（dKO小鼠）前脑中早老素-1和早老素-2的条件性双敲除诱导最类似于神经退行性疾病，特别是阿尔茨海默病的症状，然而，在dKO脑中没有额外的淀粉样蛋白-β（A β（40）或A β（42））的沉积。在本研究中，我们彻底测量了dKO小鼠的炎症反应，这是神经退行性疾病的另一个全球症状。我们证明，与对照小鼠相比，dKO脑中的胶质细胞从早期（3个月）起就被显著激活。此外，补体C1 q α和C4（经典补体途径中的关键组分）也在dKO小鼠脑中受到刺激。抗体阵列和ELISA分析表明，细胞因子和趋化因子水平也显着增加dKO脑。此外，我们发现白细胞在6月龄开始升高，并且在9月龄时dKO小鼠血清中的多种炎症介质发生变化，表明炎症反应逐渐扩展到全身组织。这些发现证实早老素双敲除导致脑和外周的强烈炎症反应，并表明dKO小鼠可能有助于进一步了解炎症对神经退行性疾病病理过程的影响。
It has been reported that conditional double knockout of presenilin-1 and presenilin-2 in forebrain of mice (dKO mice) induce symptoms most analogous to that of neurodegenerative diseases, especially Alzheimer's disease, however, there is no deposition of extra amyloid-beta (A beta(40) or A beta(42)) in dKO brain. In the present study, we thoroughly measured the inflammatory response in dKO mice, which is another global symptom in neurodegenerative diseases. We demonstrated that glial cells were dramatically activated from early age (3 months) in dKO brain when compared with control mice. In addition, complement C1q alpha and C4, the key components in the classical complement pathway, were also stimulated in dKO mice brain. Antibody array and ELISA analysis indicated that cytokine and chemokine levels were also significantly increased in dKO brain. Moreover, we found that leukocytes were elevated beginning at 6 months of age, and multiple inflammatory mediators changed in dKO mice serum at 9 months, showing that the inflammatory responses gradually expanded to systemic tissue. These findings confirm that presenilins double knockout results in robust inflammatory response both in brain and in periphery and suggest that dKO mice may be useful to further understand the effects of inflammation on the pathological processes of neurodegenerative diseases.