由单一聚集反应产生的淀粉样蛋白-β聚集体的不同毒性机制
Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.
摘要(中文译文)
淀粉样蛋白β1-42（Aβ42）聚集是阿尔茨海默病（AD）最早的病理征象之一。本研究在单分子水平上表征了Aβ42在多个聚集阶段的种类，并在小鼠器官型脑切片中检测了其毒性，观察到AD细胞期的多个方面呈现阶段依赖性重现。在Aβ42聚集的滞后期形成的聚集体升高了神经元基线钙水平并损害了长时程增强（LTP），同时促进小胶质细胞稳态退出及向疾病相关小胶质细胞（DAM）状态的转变。相反，在生长期富集的聚集体下调了稳态小胶质细胞标志物，并诱导TLR4介导的小胶质细胞活化、细胞因子产生及补体激活，导致突触吞噬和神经元活动的严重破坏。总之，这些发现揭示结构上不同的Aβ42聚集体种类参与不同的细胞和分子通路。该框架推进了对神经退行性疾病中淀粉样蛋白毒性的机制理解，并可为联合治疗策略的设计提供依据。
Abstract
Amyloid-β 1-42 (Aβ42) aggregation is among the earliest pathological signs in Alzheimer's disease (AD). Here, we characterized Aβ42 species at several aggregation stages at the single-molecule level and examined their toxicity in murine organotypic brain slices, where we observed a stage-dependent recapitulation of multiple aspects of the cellular phase of AD. Aggregates formed during the lag phase of the Aβ42 aggregation elevated neuronal baseline Ca levels and impaired long-term potentiation (LTP), while promoting microglial homeostatic exit and transition to disease-associated microglia (DAM) state. In contrast, aggregates enriched during the growth phase downregulated homeostatic microglial markers and induced TLR4-mediated microglial activation, cytokine production, and complement activation, leading to synaptic engulfment and severe disruption of neuronal activity. Together, these findings reveal that structurally distinct Aβ42 aggregate species engage different cellular and molecular pathways. This framework advances mechanistic understanding of amyloid toxicity in neurodegeneration and could inform the design of combination therapeutic strategies.
如何引用
AMA
Vanya Metodieva, Sybille Marchese, Pietro Esposito, John S H Danial, Andrea Di Falco, Suman De, et al. Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117595.
APA
Vanya Metodieva, Sybille Marchese, Pietro Esposito, John S H Danial, Andrea Di Falco, Suman De, et al (2026). Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117595
GB/T 7714
Vanya Metodieva, Sybille Marchese, Pietro Esposito, John S H Danial, Andrea Di Falco, Suman De, et al. Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117595.
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