Georg-August-University Goettingen, University Medicine Goettingen, Division of Molecular Psychiatry, 37075 Goettingen, Germany.
Acta Neuropathol Commun. 2013 Sep 6;1:56. doi: 10.1186/2051-5960-1-56.
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.
阿尔茨海默病（AD）中的淀粉样蛋白假说认为，β 淀粉样蛋白（Aβ）沉积在触发神经原纤维缠结、细胞丢失、血管损伤和记忆下降等下游事件中起作用。在过去的几年中，N 端截断的 Aβ 肽，特别是 N 端截断的焦谷氨酸 AβpE3-42，已被广泛研究。与全长 Aβ1-42 和 Aβ1-40 一起，N 端截断的 AβpE3-42 和 Aβ4-42 是 AD 大脑中的主要变体。尽管 Aβ4-42 已经被研究了很长时间，但缺乏研究来解决 AβpE3-42 或 Aβ4-42 是否可能先于 AD 病理学中的另一种的问题。
使用针对 N 端截断的 Aβ 不同 N 末端的不同 Aβ 抗体，我们发现，在斑块形成之前，在 AD 的转基因小鼠模型中，Aβ4-x 先于 AβpE3-x 在内神经元内积累。新型 Aβ4-x 免疫反应性抗体 NT4X-167 检测到源自 N 端截断的 Aβ 种的高分子量聚集体。虽然 NT4X-167 在体外显著挽救了 Aβ4-42 的毒性，但对 Aβ1-42 或 AβpE3-42 的毒性没有有益的影响。Aβ 第 4 位的苯丙氨酸对抗体结合至关重要，因为用丙氨酸或脯氨酸替换完全阻止了结合。尽管在 5XFAD 转基因小鼠中使用 NT4X-167 观察到淀粉样斑块，但在散发性 AD 患者和具有北极、瑞典和早老素-1 PS1Δ9 突变的家族病例的脑内几乎没有与斑块反应。在所有伴有脑淀粉样血管病的 AD 病例中，血管中均观察到一致的染色。与其他常见神经退行性疾病中典型的其他聚集物无交叉反应性，表明 NT4X-167 染色是 AD 的特异性。
在公认的 5XFAD AD 小鼠模型中，Aβ4-x 先于 AβpE3-x，这突显了 N 端截断的 Aβ 种在 AD 病理学中的重要性。因此，NT4X-167 是第一个与 Aβ4-x 反应的抗体，是阿尔茨海默病研究的新工具。
