Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease
Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease
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DOI：
10.1016/s0002-9440(10)64085-0
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发表时间：
2001-04-01
影响因子：
6
通讯作者：
Duff, K
中科院分区：
文献类型：
--
作者：
Matsuoka, Y;Picciano, M;Duff, K
淀粉样前体蛋白（APP）以及早老素 -1和 -2基因（PS -1， -2）的突变会引发阿尔茨海默病（AD）。携带这两种突变基因（PS/APP）的小鼠在幼年时就会形成由β - 淀粉样蛋白（Aβ）组成的类似阿尔茨海默病的沉积物。在这项研究中，我们探究了Aβ沉积与免疫反应之间的关联。3个月时，额叶皮质中就可见纤维状和非纤维状Aβ（弥散性）沉积物，并且淀粉样蛋白负荷随年龄增长急剧增加。纤维状Aβ沉积物的数量在研究的最大年龄（2.5岁）时仍在增加，而1岁以上小鼠的弥散性沉积物数量变化不太明显。活化的小胶质细胞和星形胶质细胞与淀粉样蛋白负荷同步增加，并且通常与沉积物密切相关。环氧合酶 -2是一种参与前列腺素途径的炎症反应分子，在一些与纤维状沉积物相关的星形胶质细胞中表达上调。补体成分Iq是一种免疫反应成分，与纤维状Aβ强烈共定位，但在一些与斑块相关的小胶质细胞中也表达上调。这些结果表明：i）在衰老的PS/APP小鼠大脑中，由纤维状Aβ组成的淀粉样蛋白比例不断增加；ii）小胶质细胞和星形胶质细胞被纤维状和弥散性Aβ激活；iii）在PS/APP小鼠中，环氧合酶 -2和补体成分1q的水平随着纤维状Aβ的形成而增加。
Mutations in the amyloid precursor protein (APP) and presenilin-1 and -2 genes (PS-I, -2) cause Alzheimer's disease (AD), Mice carrying both mutant genes (PS/APP) develop AD-like deposits composed of beta -amyloid (A beta) at an early age. In this study, we have examined how A beta deposition is associated with immune responses. Both fibrillar and nonfibrillar A beta (diffuse) deposits were visible in the frontal cortex by 3 months, and the amyloid load increased dramatically with age. The number of fibrillar A beta deposits increased up to the oldest age studied (2.5 years old), whereas there were less marked changes in the number of diffuse deposits in mice over 1 year old. Activated microglia and astrocytes increased synchronously with amyloid burden and were, in general, closely associated with deposits. Cyclooxygenase-2, an inflammatory response molecule involved in the prostaglandin pathway, was up-regulated in astrocytes associated with some fibrillar deposits. Complement component Iq, an immune response component, strongly colocalized with fibrillar A beta, but was also up-regulated in some plaque-associated microglia These results show: i) an increasing proportion of amyloid is composed of frbrillar A beta in the aging PS/APP mouse brain; ii) microglia and astrocytes are activated by both fibrillar and diffuse A beta; and iii) cyclooxygenase-a and complement component 1q levels increase in response to the formation of fibrillar A beta in PS/APP mice.