阿茲海默氏病患者腦萃取物衍生之乙型類澱粉蛋白寡聚體擴增與結構鑑定
Amplification and Structural Characterization of Beta Amyloid Oligomers Derived from Brain Extracts of Alzheimer's Disease Patients
國立臺灣大學化學系 陳振中 教授
中央研究院基因體中心 陳韻如 研究員
本研究為國立臺灣大學陳振中教授研究團隊與中央研究院陳韻如（Ruby Chen）博士研究團隊之合作成果，研究主題聚焦於與神經退化疾病相關之 β-類澱粉蛋白（Aβ）寡聚體及其分子伴侶之交互作用機制，研究成果已發表於 Chemistry – A European Journal（2025）
本研究針對阿茲海默症研究中的一項核心難題：Aβ 寡聚體具有高度短暫性與結構異質性，因此難以穩定分離與進行分子層級結構分析。雙方團隊透過密切合作，建立了以 reverse micelle（反向微胞）為基礎之奈米侷限實驗平台，可有效穩定 Aβ 寡聚體，並促進早期蛋白質–蛋白質與蛋白質–離子交互作用之研究。藉由此平台，成功製備包含 Aβ、鋅離子與 TDP-43 蛋白片段之穩定寡聚複合體。
是次合作的重要成果之一，是首次直接於分子層級證實 Aβ40 寡聚體可與神經退化疾病相關之 TDP-43 蛋白片段形成穩定複合體。研究中利用同位素標記結合固態核磁共振技術（特別是 REDOR NMR），成功觀察到 Aβ40 與 TDP-43 間之近距離分子接觸。此外，本研究亦發現鋅離子會選擇性改變 Aβ 寡聚體中特定 glutamate 殘基之化學環境，顯示環境因子可能調控具毒性類澱粉蛋白寡聚體之結構分布與聚集行為。上述成果對於理解神經退化疾病中類澱粉蛋白早期聚集與交互作用機制具有重要意義。
此研究計劃充分展現雙方研究團隊之互補性與加乘效果。中央研究院陳韻如博士研究團隊長期專精於類澱粉蛋白與神經退化疾病相關研究，負責 TDP-43 蛋白片段之製備、純化及同位素標記樣品之建立，並提供有關蛋白聚集行為、生物學背景與疾病相關機制的重要知識與實驗設計。
國立臺灣大學陳振中教授研究團隊則負責 reverse micelle 平台之建立與應用、Aβ 寡聚體之製備與分析，以及固態核磁共振量測、REDOR NMR 分析與其他生物物理及生化實驗。相關核磁共振與生物分析工作主要由陳教授實驗室之學生完成。臺大團隊進一步負責高解析結構數據之取得與解析，使本研究得以從分子層級探討寡聚蛋白複合體之結構特徵。
此合作之成功高度仰賴雙方研究專長之整合。中央研究院提供先進之蛋白質製備與神經退化疾病研究經驗，而國立臺灣大學則提供固態核磁共振技術與奈米侷限系統之方法學優勢。透過本次合作，雙方成功建立跨越結構化學、生物物理與神經退化疾病研究之跨領域合作模式，不僅深化了對類澱粉蛋白相關分子交互作用之理解，也展現 reverse micelle 系統作為研究瞬態蛋白複合體平台之潛力。
This collaborative research between the laboratory of Prof. Jerry C. C. Chan at National Taiwan University and Dr. Yun-Ru (Ruby) Chen at Academia Sinica focused on elucidating the molecular interactions between β-amyloid (Aβ) peptides and their molecular associates relevant to neurodegenerative diseases, particularly Alzheimer’s disease. The study was published as “Oligomeric Protein Complexes Formed by Beta Amyloid Peptides and Their Molecular Associates” in Chemistry – A European Journal (2025).
The project addressed a major challenge in Alzheimer’s disease research: the transient and heterogeneous nature of oligomeric Aβ species, which makes them difficult to isolate and characterize structurally. Through close collaboration between the two research teams, we established a reverse-micelle-based experimental platform capable of stabilizing oligomeric Aβ assemblies and facilitating the investigation of early-stage protein–protein and protein–ion interactions under confined nanoscale environments. This platform enabled the preparation of structurally stable oligomeric complexes involving Aβ peptides, zinc ions, and TDP-43 protein fragments.
A major achievement of this work was the direct experimental demonstration that oligomeric Aβ40 can form stable molecular complexes with a TDP-43 fragment associated with neurodegenerative diseases. Using isotope-assisted solid-state NMR techniques, particularly REDOR NMR measurements, the study provided molecular-level evidence for close intermolecular contacts between Aβ40 and TDP-43 within oligomeric assemblies. The work also demonstrated that zinc ions induce selective structural perturbations at specific glutamate residues of Aβ oligomers, revealing how environmental factors may regulate the conformational landscape of toxic amyloid species. These findings provide important mechanistic insights into how molecular partners modulate the structure and behavior of amyloid oligomers during the early stages of aggregation.
Importantly, the collaboration achieved strong complementarity between the expertise of the two teams. Dr. Ruby Chen’s group at Academia Sinica contributed extensive expertise in amyloid biology and protein preparation. In particular, her laboratory prepared and purified the TDP-43 protein fragments, including isotope-labeled samples required for the intermolecular NMR experiments. Her group also contributed essential knowledge regarding amyloid aggregation behavior, biological relevance, and experimental design related to neurodegenerative disease mechanisms.
Prof. Jerry C. C. Chan’s group at National Taiwan University contributed the development and application of the reverse micelle platform, the preparation and characterization of oligomeric assemblies, solid-state NMR measurements, REDOR NMR analysis, and other biophysical and bioassay investigations carried out by students in the laboratory. The NTU team was responsible for acquiring and interpreting the high-resolution structural data that enabled molecular-level characterization of the oligomeric protein complexes.
The success of this project relied heavily on the integration of complementary expertise from both institutions. Academia Sinica provided advanced biochemical and protein-preparation capabilities, while National Taiwan University contributed advanced solid-state NMR methodology and nanoscale confinement strategies. Through this collaboration, the two teams established an effective interdisciplinary framework bridging structural chemistry, biophysics, and neurodegenerative disease research. The resulting work not only advanced the mechanistic understanding of amyloid-associated molecular interactions but also demonstrated the potential of reverse micelle systems as a versatile platform for studying transient protein complexes relevant to neurodegenerative disorders.