N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody.
N-truncated Abeta starting with position four: early intraneuronal accumulation and rescue of toxicity using NT4X-167, a novel monoclonal antibody.
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DOI：
10.1186/2051-5960-1-56
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发表时间：
2013-09-06
影响因子：
7.1
通讯作者：
Bayer TA
中科院分区：
文献类型：
--
作者：
Antonios G;Saiepour N;Bouter Y;Richard BC;Paetau A;Verkkoniemi-Ahola A;Lannfelt L;Ingelsson M;Kovacs GG;Pillot T;Wirths O;Bayer TA
阿尔茨海默病（Alzheimer disease，AD）中的淀粉样蛋白假说认为淀粉样蛋白β肽（amyloid β peptide，Aβ）沉积是引发神经元缠结、细胞丢失、血管损伤和记忆力下降等下游事件的原因。近年来，N-截短的Aβ肽尤其是N-截短的焦谷氨酸Aβ pE 3 -42得到了广泛的研究。与全长Aβ1-42和Aβ1-40一起，N截短的Aβ pE 3 -42和Aβ4-42是AD脑中的主要变体。虽然Aβ4-42已经被发现了很长时间，但缺乏研究来解决Aβ pE 3 -42或Aβ4-42在阿尔茨海默病病理学中是否先于另一个的问题。使用对N截短Aβ的不同N末端具有特异性的不同Aβ抗体，我们发现在斑块形成之前，Aβ4-x先于AD转基因小鼠模型中的Aβ pE 3-x神经元内蓄积。新型Aβ4-x免疫反应性抗体NT 4X-167检测到来自N-截短Aβ物质的高分子量聚集体。虽然NT 4X-167在体外显著挽救Aβ4-42毒性，但未观察到对Aβ1-42或Aβ pE 3 -42毒性的有益作用。Aβ第4位的苯丙氨酸对于抗体结合是必不可少的，因为它被丙氨酸或脯氨酸取代完全阻止了结合。尽管在5XFAD转基因小鼠中使用NT 4X-167观察到淀粉样蛋白斑块，但它几乎不与散发性AD患者和具有北极、瑞典和早老素-1 PS1Δ9突变的家族性病例的脑中的斑块反应。在所有伴有脑淀粉样血管病的AD病例的血管中观察到一致的染色。与其他常见神经退行性疾病的典型聚集体没有交叉反应性，表明NT 4X-167染色对AD具有特异性。在公认的5XFAD AD小鼠模型中，Aβ4-x先于Aβ pE 3-x，这强调了N截短物质在AD病理学中的重要性。因此，NT 4X-167是第一个与Aβ4-x反应的抗体，代表了阿尔茨海默病研究的新工具。
The amyloid hypothesis in Alzheimer disease (AD) considers amyloid β peptide (Aβ) deposition causative in triggering down-stream events like neurofibrillary tangles, cell loss, vascular damage and memory decline. In the past years N-truncated Aβ peptides especially N-truncated pyroglutamate AβpE3-42 have been extensively studied. Together with full-length Aβ1–42 and Aβ1–40, N-truncated AβpE3-42 and Aβ4–42 are major variants in AD brain. Although Aβ4–42 has been known for a much longer time, there is a lack of studies addressing the question whether AβpE3-42 or Aβ4–42 may precede the other in Alzheimer’s disease pathology. Using different Aβ antibodies specific for the different N-termini of N-truncated Aβ, we discovered that Aβ4-x preceded AβpE3-x intraneuronal accumulation in a transgenic mouse model for AD prior to plaque formation. The novel Aβ4-x immunoreactive antibody NT4X-167 detected high molecular weight aggregates derived from N-truncated Aβ species. While NT4X-167 significantly rescued Aβ4–42 toxicity in vitro no beneficial effect was observed against Aβ1–42 or AβpE3-42 toxicity. Phenylalanine at position four of Aβ was imperative for antibody binding, because its replacement with alanine or proline completely prevented binding. Although amyloid plaques were observed using NT4X-167 in 5XFAD transgenic mice, it barely reacted with plaques in the brain of sporadic AD patients and familial cases with the Arctic, Swedish and the presenilin-1 PS1Δ9 mutation. A consistent staining was observed in blood vessels in all AD cases with cerebral amyloid angiopathy. There was no cross-reactivity with other aggregates typical for other common neurodegenerative diseases showing that NT4X-167 staining is specific for AD. Aβ4-x precedes AβpE3-x in the well accepted 5XFAD AD mouse model underlining the significance of N-truncated species in AD pathology. NT4X-167 therefore is the first antibody reacting with Aβ4-x and represents a novel tool in Alzheimer research.
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影响因子：
12.7
作者：
Bouter Y;Dietrich K;Wittnam JL;Rezaei-Ghaleh N;Pillot T;Papot-Couturier S;Lefebvre T;Sprenger F;Wirths O;Zweckstetter M;Bayer TA
通讯作者：
Bayer TA
DOI：
10.1016/s0140-6736(20)32205-4
发表时间：
2021-04-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Scheltens P;De Strooper B;Kivipelto M;Holstege H;Chételat G;Teunissen CE;Cummings J;van der Flier WM
通讯作者：
van der Flier WM
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
16.6
作者：
Haupt, Christian;Leppert, Joerg;Faendrich, Marcus
通讯作者：
Faendrich, Marcus
影响因子：
2.9
作者：
He, WL;Barrow, CJ
通讯作者：
Barrow, CJ