A calcium-sensitive antibody isolates soluble amyloid-β aggregates and fibrils from Alzheimer's disease brain.
A calcium-sensitive antibody isolates soluble amyloid-β aggregates and fibrils from Alzheimer's disease brain.
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DOI：
10.1093/brain/awac023
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发表时间：
2022-07-29
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在阿尔茨海默病中，淀粉样蛋白β多肽的水溶性寡聚体可能是淀粉样蛋白β的主要神经毒性形式，引发下游事件，包括tau过度磷酸化、神经突触/突触损伤、小胶质细胞增生和神经元丢失。合成寡聚淀粉样蛋白-β已被广泛研究，但对人脑中天然寡聚淀粉样蛋白-β的生物化学知之甚少，尽管它比简单的合成多肽更有效，并且由截短和修饰的淀粉样蛋白-β单体组成。我们推测针对神经毒性寡聚淀粉样蛋白-β的单抗可以用来分离它以进行进一步的研究。在这里，我们报道了一种针对合成的寡聚淀粉样蛋白-β的独特的人类单抗(B24)，它能有效地预防阿尔茨海默病脑低聚体淀粉样蛋白-β诱导的海马长时程增强的损害。B24与天然和合成的寡聚体淀粉样蛋白-β和部分淀粉样斑块结合，但仅在钙离子存在的情况下。B24结合需要淀粉样蛋白-βN末端。羟基磷灰石层析显示，天然低聚淀粉样蛋白-β对钙离子有很强的亲和力。我们利用B24结合可逆的钙依赖性，从阿尔茨海默病脑提取物中分离出低聚淀粉样蛋白-β，并进行了非变性免疫亲和分离。出乎意料的是，免疫纯化的材料含有电子显微镜下可见的淀粉样纤维，并可进行进一步的结构表征。B24纯化的人低聚淀粉样蛋白-β抑制小鼠海马长时程增强。这些发现确定了一种钙依赖的方法来纯化生物活性脑低聚淀粉样蛋白-β，其中至少部分似乎是纤维状的。斯特恩等人。开发一种新的针对神经毒性β-淀粉样肽低聚体的单抗。这种抗体具有独特的钙敏感特性，可以从阿尔茨海默病患者的脑中分离出可溶的淀粉样β-聚集体，而不会发生变性，其中一些呈现纤维状形态。
Aqueously soluble oligomers of amyloid-β peptide may be the principal neurotoxic forms of amyloid-β in Alzheimer’s disease, initiating downstream events that include tau hyperphosphorylation, neuritic/synaptic injury, microgliosis and neuron loss. Synthetic oligomeric amyloid-β has been studied extensively, but little is known about the biochemistry of natural oligomeric amyloid-β in human brain, even though it is more potent than simple synthetic peptides and comprises truncated and modified amyloid-β monomers. We hypothesized that monoclonal antibodies specific to neurotoxic oligomeric amyloid-β could be used to isolate it for further study. Here we report a unique human monoclonal antibody (B24) raised against synthetic oligomeric amyloid-β that potently prevents Alzheimer’s disease brain oligomeric amyloid-β-induced impairment of hippocampal long-term potentiation. B24 binds natural and synthetic oligomeric amyloid-β and a subset of amyloid plaques, but only in the presence of Ca2+. The amyloid-β N terminus is required for B24 binding. Hydroxyapatite chromatography revealed that natural oligomeric amyloid-β is highly avid for Ca2+. We took advantage of the reversible Ca2+-dependence of B24 binding to perform non-denaturing immunoaffinity isolation of oligomeric amyloid-β from Alzheimer’s disease brain-soluble extracts. Unexpectedly, the immunopurified material contained amyloid fibrils visualized by electron microscopy and amenable to further structural characterization. B24-purified human oligomeric amyloid-β inhibited mouse hippocampal long-term potentiation. These findings identify a calcium-dependent method for purifying bioactive brain oligomeric amyloid-β, at least some of which appears fibrillar. Stern et al. develop a new monoclonal antibody specific to neurotoxic oligomers of amyloid-beta peptide. A unique calcium-sensitive property of this antibody enables isolation of soluble amyloid-beta aggregates from Alzheimer’s disease brain without denaturation, some of which exhibit fibrillar morphology.
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DOI：
10.1186/s13195-021-00813-8
发表时间：
2021-04-17
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Swanson CJ;Zhang Y;Dhadda S;Wang J;Kaplow J;Lai RYK;Lannfelt L;Bradley H;Rabe M;Koyama A;Reyderman L;Berry DA;Berry S;Gordon R;Kramer LD;Cummings JL
通讯作者：
Cummings JL
DOI：
10.1126/science.aao2825
发表时间：
2017-10-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gremer L;Schölzel D;Schenk C;Reinartz E;Labahn J;Ravelli RBG;Tusche M;Lopez-Iglesias C;Hoyer W;Heise H;Willbold D;Schröder GF
通讯作者：
Schröder GF
影响因子：
64.8
作者：
Qiang W;Yau WM;Lu JX;Collinge J;Tycko R
通讯作者：
Tycko R
DOI：
10.1523/jneurosci.0203-11.2011
发表时间：
2011-05-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Li S;Jin M;Koeglsperger T;Shepardson NE;Shankar GM;Selkoe DJ
通讯作者：
Selkoe DJ
影响因子：
25
作者：
Nilsberth, C;Westlind-Danielsson, A;Lannfelt, L
通讯作者：
Lannfelt, L