Localization of MAP1-LC3 in Vulnerable Neurons and Lewy Bodies in Brains of Patients With Dementia With Lewy Bodies
Localization of MAP1-LC3 in Vulnerable Neurons and Lewy Bodies in Brains of Patients With Dementia With Lewy Bodies
复制标题
DOI：
10.1097/nen.0b013e318211c86a
复制
发表时间：
2011-04-01
影响因子：
3.2
通讯作者：
Iseki, Eizo
中科院分区：
文献类型：
--
作者：
Higashi, Shinji;Moore, Darren J.;Iseki, Eizo
有新的证据表明自噬-溶酶体途径在路易体病的发病机制中的作用。我们使用抗Ras相关蛋白Rab-7 B（Rab 7 B）、溶酶体相关膜蛋白2（LAMP 2）和微管相关蛋白1A/1B轻链3（LC 3）的抗体，研究了路易体痴呆（DLB）、阿尔茨海默病（AD）和对照组患者脑中自噬-溶酶体通路相关蛋白的潜在神经病理学和生化改变。在DLB，但不是在对照组的大脑，有大Rab 7 B免疫反应性内体颗粒。LC 3免疫反应性增加，在DLB大脑的脆弱地区相对于控制大脑，计算机细胞计数分析显示，LC 3水平更大的内嗅皮层和杏仁核的DLB大脑比对照组。在DLB脑的内嗅皮层中Rab 7 B水平增加，而LAMP 2水平降低。相比之下，在AD脑中仅发现LAMP 2水平相对于对照降低。LC 3与几种类型的Lewy病理学广泛共定位; LAMP 2定位于脑干型Lewy小体的外周或外部; Rab 7 B与Lewy病理学不共定位。免疫印迹分析表明，自噬体LC 3-II亚型在DLB脑的洗涤剂不溶性组分中的特异性积累。这些结果支持自噬-溶酶体途径在DLB发病机制中的潜在作用。
There is emerging evidence implicating a role for the autophagy-ysosome pathway in the pathogenesis of Lewy body disease. We investigated potential neuropathologic and biochemical alterations of autophagy-lysosome pathway-related proteins in the brains of patients with dementia with Lewy bodies (DLB), Alzheimer disease (AD), and control subjects using antibodies against Ras-related protein Rab-7B (Rab7B), lysosomal-associated membrane protein 2 (LAMP2), and microtubule-associated protein 1A/1B light chain 3 (LC3). In DLB, but not in control brains, there were large Rab7B-immunoreactive endosomal granules. LC3 immunoreactivity was increased in vulnerable areas of DLB brains relative to that in control brains; computerized cell counting analysis revealed that LC3 levels were greater in the entorhinal cortex and amygdala of DLB brains than in controls. Rab7B levels were increased, and LAMP2 levels were decreased in the entorhinal cortex of DLB brains. In contrast, only a decrease in LAMP2 levels versus controls was found in AD brains. LC3 widely colocalized with several types of Lewy pathology; LAMP2 localized to the periphery or outside of brainstem-type Lewy bodies; Rab7B did not colocalize with Lewy pathology. Immunoblot analysis demonstrated specific accumulation of the autophagosomal LC3-II isoform in detergent-insoluble fractions from DLB brains. These results support a potential role for the autophagy-lysosome pathway in the pathogenesis of DLB.