Familial Danish dementia: co-existence of Danish and Alzheimer amyloid subunits (ADan AND A{beta}) in the absence of compact plaques.
Familial Danish dementia: co-existence of Danish and Alzheimer amyloid subunits (ADan AND A{beta}) in the absence of compact plaques.
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家族性丹麦痴呆：丹麦淀粉样蛋白亚基和阿尔茨海默淀粉样蛋白亚基（ADan 和 A{β}）在没有致密斑块的情况下共存。
DOI：
10.1074/jbc.m504038200
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
Ghiso,Jorge
中科院分区：
文献类型：
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作者：
Tomidokoro,Yasushi;Lashley,Tammaryn;Rostagno,Agueda;Neubert,ThomasA;Bojsen-Møller,Marie;Braendgaard,Hans;Plant,Gordon;Holton,Janice;Frangione,Blas;Révész,Tamas;Ghiso,Jorge
家族性丹麦痴呆是一种早发常染色体显性神经退行性疾病，与bri2基因的遗传缺陷有关，临床特征为痴呆和共济失调。两种不相关分子（丹麦淀粉样蛋白（ADan）和β-淀粉样蛋白（Aβ））的大脑淀粉样蛋白和前淀粉样蛋白沉积，致密斑块的缺失以及与阿尔茨海默病（AD）观察到的难以区分的神经原纤维变性是该疾病的主要神经病理学特征。提取的淀粉样蛋白和前淀粉样蛋白的生化分析表明，随着沉积物溶解度的降低，提取肽的异质性和复杂性呈指数级增加。非纤原性沉积物主要由完整的ADan-(1-34)及其n端修饰（焦谷氨酸）对应物与Aβ-(1-42)和Aβ-(4-42)以1:1的比例混合组成。翻译后的修饰，谷氨酸到焦谷氨酸，不存在可溶性循环ADan。在淀粉样蛋白组分中，ADan在N端和C端高度低聚化和异质性，并且在完整时，其N端被翻译后修饰（焦谷氨酸），而Aβ主要是Aβ-(4-42)。在所有病例中，a β-(X-40)的存在都可以忽略不计，这是一个令人惊讶的发现，因为a β40在散发性和家族性AD、唐氏综合征和正常衰老中观察到的血管沉积物中普遍存在。这两个淀粉样蛋白亚基的存在是否对疾病表型是必要的，还是仅仅反映了一种构象模仿，仍有待阐明；尽管如此，在合成肽的体外配体印迹分析中，证明了ADan低聚物与a β分子之间的特异性相互作用。在广泛的神经纤维变性存在的情况下，致密斑块的缺失强烈表明，致密斑块作为AD诊断的基础病变，并不是痴呆机制所必需的。
Familial Danish dementia is an early onset autosomal dominant neurodegenerative disorder linked to a genetic defect in theBRI2gene and clinically characterized by dementia and ataxia. Cerebral amyloid and preamyloid deposits of two unrelated molecules (Danish amyloid (ADan) and β-amyloid (Aβ)), the absence of compact plaques, and neurofibrillary degeneration indistinguishable from that observed in Alzheimer disease (AD) are the main neuropathological features of the disease. Biochemical analysis of extracted amyloid and preamyloid species indicates that as the solubility of the deposits decreases, the heterogeneity and complexity of the extracted peptides exponentially increase. Nonfibrillar deposits were mainly composed of intact ADan-(1-34) and its N-terminally modified (pyroglutamate) counterpart together with Aβ-(1-42) and Aβ-(4-42) in ∼1:1 mixture. The post-translational modification, glutamate to pyroglutamate, was not present in soluble circulating ADan. In the amyloid fractions, ADan was heavily oligomerized and highly heterogeneous at the N and C terminus, and, when intact, its N terminus was post-translationally modified (pyroglutamate), whereas Aβ was mainly Aβ-(4-42). In all cases, the presence of Aβ-(X-40) was negligible, a surprising finding in view of the prevalence of Aβ40 in vascular deposits observed in sporadic and familial AD, Down syndrome, and normal aging. Whether the presence of the two amyloid subunits is imperative for the disease phenotype or just reflects a conformational mimicry remains to be elucidated; nonetheless, a specific interaction between ADan oligomers and Aβ molecules was demonstratedin vitroby ligand blot analysis using synthetic peptides. The absence of compact plaques in the presence of extensive neuro fibrillar degeneration strongly suggests that compact plaques, fundamental lesions for the diagnosis of AD, are not essential for the mechanism of dementia.