Neuropathology and pathogenesis of encephalitis following amyloid-β immunization in Alzheimer's disease
Neuropathology and pathogenesis of encephalitis following amyloid-β immunization in Alzheimer's disease
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DOI：
10.1111/j.1750-3639.2004.tb00493.x
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发表时间：
2004-01-01
期刊：
影响因子：
6.4
通讯作者：
Costa-Jussá, F
中科院分区：
文献类型：
--
作者：
Ferrer, I;Rovira, MB;Costa-Jussá, F
与未处理的转基因动物相比，阿尔茨海默病（AD）中类似斑块的β -淀粉样蛋白沉积导致淀粉样蛋白负担减少。在一项针对阿尔茨海默病的随机试点研究中，淀粉样蛋白- β肽免疫已经开始。然而，少数患者出现与脑膜脑炎相符的神经系统并发症，一名患者死亡；审判已经停止了。该患者的神经病理学检查显示脑膜脑炎，局灶性弥漫性和神经性斑块数量不典型，但未见血管淀粉样蛋白，神经原纤维缠结和神经丝中未见tau病理消退。本神经病理学研究报告了第二例阿尔茨海默病中淀粉样蛋白- β肽免疫后的脑膜脑炎，并旨在探索与淀粉样蛋白沉积消退相关的tau病理减少的机制，以及免疫后炎症反应可能涉及的分子基础。炎性浸润主要由CD8+、CD4+、CD3+、CD5+淋巴细胞组成，很少有CD7+淋巴细胞，而B淋巴细胞和T细胞毒性细胞CD16、CD57、TIA和grase阴性。特征性神经病理表现为弥漫性和神经性斑块的局灶性消失，但淀粉样血管病不存在，存在少量被活跃的小胶质细胞包围的极致密（塌陷）斑块，多核巨细胞充满致密的Abeta（42）和Abeta(40)，此外还有严重的小脑血管疾病和多发性皮质出血。淀粉样蛋白负荷的减少伴随着低淀粉样蛋白相关的氧化应激反应（超氧化物歧化酶-1:SOD-1表达的减少），以及参与tau磷酸化的应激激活蛋白激酶/c-Jun n -末端激酶（SAPK/JNK）和p38激酶的局部抑制。这些结果支持阿尔茨海默病中tau蛋白磷酸化的淀粉样级联反应，即tau蛋白磷酸化依赖于神经斑块中的β -淀粉样蛋白沉积，而不是神经原纤维缠结和线中的tau蛋白磷酸化。此外，淀粉样蛋白的减少伴随着pa28 α / β诱导剂、免疫蛋白酶体LMP7、LMP2和MECL1亚基在塌陷斑块周围的小胶质细胞和炎症细胞以及多核巨细胞中的表达增加。免疫蛋白酶体亚基表达伴随着MHC I类分子的局部呈递。源自β -淀粉样蛋白加工的抗原肽的释放可能会增强t细胞炎症反应，这是淀粉样蛋白- β肽免疫后脑膜脑炎的原因。
beta-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non-treated transgenic animals. Immunization with amyloid-beta peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis, and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid, nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of meningoencephalitis following immunization with amyloid-beta peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation with amyloid deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+,CD4+,CD3+,CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense (collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense Abeta(42) and Abeta(40), in addition to severe small cerebral blood vessel disease and multiple cortical hemorrhages. Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1: SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau dependent on beta-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28alpha/beta inductor, and of LMP7, LMP2 and MECL1 subunits of the immunoproteasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells. Immunoproteasome subunit expression was accompanied by local presentation of MHC class I molecules. Release of antigenic peptides derived from beta-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-beta peptide immunization.