BACE2 Expression Increases in Human Neurodegenerative Disease
BACE2 Expression Increases in Human Neurodegenerative Disease
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DOI：
10.1016/j.ajpath.2011.09.034
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发表时间：
2012-01-01
影响因子：
6
通讯作者：
Murphy, M. Paul
中科院分区：
文献类型：
--
作者：
Holler, Christopher J.;Webb, Robin L.;Murphy, M. Paul
β - 分泌酶是产生β - 淀粉样蛋白（Aβ）肽的限速酶活性，是阿尔茨海默病（AD）治疗的主要靶点。该酶有两种形式：β - 位点Aβ前体蛋白裂解酶（BACE）1和BACE2。尽管BACE1在阿尔茨海默病晚期增加，但对BACE2知之甚少。我们对临床前到晚期阿尔茨海默病患者（包括遗忘型轻度认知障碍患者）、年龄匹配的对照组、额颞叶痴呆病例以及唐氏综合征患者进行了BACE2的详细检测。早在临床前阿尔茨海默病阶段，BACE2蛋白和酶活性就已增加，并且在神经元和星形胶质细胞中被发现。尽管总BACE2 mRNA水平未改变，但BACE2剪接形式C（缺失外显子7）的mRNA与BACE2蛋白和活性平行增加。BACE1和BACE2在所有水平上都密切相关，这表明它们的调控机制可能在很大程度上是相同的。BACE2在额颞叶痴呆中也升高，但在唐氏综合征中不升高，即使在有大量Aβ沉积的患者中也是如此。因此，两种形式的β - 分泌酶的表达是相关的，并且可能在人类神经系统疾病中共同发挥作用。更好地理解BACE1和BACE2的正常功能以及它们在不同疾病状态下如何变化，对于阿尔茨海默病治疗的未来发展至关重要。（《美国病理学杂志》2012年180卷：337 - 350页；DOI: 10.1016/j.ajpath.2011.09.034）
beta-Secretase, the rate-limiting enzymatic activity in the production of the amyloid-beta (A beta) peptide, is a major target of Alzheimer's disease (AD) therapeutics. There are two forms of the enzyme: beta-site A beta precursor protein cleaving enzyme (BACE) 1 and BACE2. Although BACE1 increases in late-stage AD, little is known about BACE2. We conducted a detailed examination of BACE2 in patients with preclinical to late-stage AD, including amnestic mild cognitive impairment, and age-matched controls, cases of frontotemporal dementia, and Down's syndrome. BACE2 protein and enzymatic activity increased as early as preclinical AD and were found in neurons and astrocytes. Although the levels of total BACE2 mRNA were unchanged, the mRNA for BACE2 splice form C (missing exon 7) increased in parallel with BACE2 protein and activity. BACE1 and BACE2 were strongly correlated with each other at all levels, suggesting that their regulatory mechanisms may be largely shared. BACE2 was also elevated in frontotemporal dementia but not in Down's syndrome, even in patients with substantial A beta deposition. Thus, expression of both forms of beta-secretase are linked and may play a combined role in human neurologic disease. A better understanding of the normal functions of BACE1 and BACE2, and how these change in different disease states, is essential for the future development of AD therapeutics. (Am J Pathol 2012 180:337-350; DOI: 10.1016/j.ajpath.2011.09.034)