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在 Aβ斑块处，营养不良神经突和小胶质细胞中氧化还原状态的同步成像表明溶酶体积累而非小胶质细胞与氧化应激增加相关。

Simultaneous imaging of redox states in dystrophic neurites and microglia at Aβ plaques indicate lysosome accumulation not microglia correlate with increased oxidative stress.

机构信息

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, V6T 1Z3, Canada.

Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, V6T 1Z3, Canada.

出版信息

Redox Biol. 2022 Oct;56:102448. doi: 10.1016/j.redox.2022.102448. Epub 2022 Aug 20.

DOI:10.1016/j.redox.2022.102448
PMID:36037587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9440309/
Abstract

The inter-relationship between microglia dynamics and oxidative stress (Ox-stress) in dystrophic neurites (DNs) at Alzheimer's Disease (AD) plaques may contribute to the pathological changes in neurons. We developed new in vivo imaging strategies to combine EGFP expression in microglia with neuronal expression of genetically encoded ratiometric redox sensors (rogRFP2 or roGFP1), and immunohistochemistry to investigate how microglia influence Ox-stress at amyloid plaques in 5xFAD AD mice. By simultaneously imaging microglia morphology and neuronal Ox-stress over time in vivo and in fixed brains we found that microglia preferentially enwrapped DNs exhibiting the greatest degree of Ox-stress. After microglia were partially depleted with the CSF1 receptor antagonist PLX3397, Ox-stress in DNs increased in a manner that was inversely correlated to the extent of coverage of the adjacent Aβ plaques by the remaining microglia. These data suggest that microglia do not create Ox-stress at Aβ plaques but instead create protective barriers around Aβ plaques possibly reducing the spread of Aβ. Intracranial injection of Aβ was sufficient to induce neuronal Ox-stress suggesting it to be the initial trigger of Ox-stress generation. Although Ox-stress is increased in DNs, neuronal survival is enhanced following microglia depletion indicating complex and multifactorial roles of microglia with both neurotoxic and neuroprotective components. Increased Ox-stress of DNs was correlated with higher LAMP1 and ubiquitin immunoreactivity supporting proposed mechanistic links between lysosomal accumulation in DNs and their intrinsic generation of Ox-stress. Our results suggest protective as well as neurotoxic roles for microglia at plaques and that the generation of Ox-stress of DNs could intrinsically be generated via lysosomal disruption rather than by microglia. In Brief: Simultaneous imaging of microglia and neuronal Ox-stress revealed a double-edged role for microglia in 5xFAD mice. Plaque associated microglia were attracted to and enwrapped Aβ plaques as well as the most highly oxidized DNs. After partial depletion of microglia, DNs were larger with greater levels of Ox-stress. Despite increased Ox-stress after microglia removal neuronal survival improved. Greater Ox-stress was correlated with increased levels of LAMP1 and ubiquitin thereby linking lysosome accumulation and Ox-stress in DNs.

摘要

在阿尔茨海默病（AD）斑块中的神经突营养不良（DNs）中，小胶质细胞动力学与氧化应激（Ox-stress）之间的相互关系可能导致神经元的病理变化。我们开发了新的体内成像策略，将小胶质细胞中的 EGFP 表达与遗传编码的比率型氧化还原传感器（rogRFP2 或 roGFP1）在神经元中的表达以及免疫组织化学结合起来，以研究小胶质细胞如何影响 5xFAD AD 小鼠中淀粉样斑块的 Ox-stress。通过同时在体内和固定脑中实时成像小胶质细胞形态和神经元 Ox-stress，我们发现小胶质细胞优先包裹显示最大程度 Ox-stress 的 DNs。在用 CSF1 受体拮抗剂 PLX3397 部分耗尽小胶质细胞后，DN 中的 Ox-stress 增加，其方式与剩余小胶质细胞对相邻 Aβ斑块的覆盖程度呈反比。这些数据表明，小胶质细胞不会在 Aβ斑块处产生 Ox-stress，而是在 Aβ斑块周围形成保护性屏障，可能会减少 Aβ的扩散。颅内注射 Aβ足以诱导神经元 Ox-stress，表明其是 Ox-stress 产生的初始触发因素。尽管 DNs 中的 Ox-stress 增加，但在小胶质细胞耗竭后神经元的存活率提高，表明小胶质细胞具有神经毒性和神经保护成分的复杂和多因素作用。DN 中 Ox-stress 的增加与 LAMP1 和泛素免疫反应性增加相关，支持了溶酶体在 DNs 中的积累与其内在产生 Ox-stress 之间的拟议机制联系。我们的结果表明，小胶质细胞在斑块处具有保护作用和神经毒性作用，并且 DNs 的 Ox-stress 产生可能内在地通过溶酶体破坏而不是通过小胶质细胞产生。简而言之：同时对小胶质细胞和神经元 Ox-stress 的成像揭示了小胶质细胞在 5xFAD 小鼠中的双重作用。斑块相关的小胶质细胞被吸引到 Aβ斑块以及氧化应激程度最高的 DNs 上，并将其包裹起来。在小胶质细胞部分耗尽后，DN 更大，Ox-stress 水平更高。尽管小胶质细胞去除后 Ox-stress 增加，但神经元的存活率提高了。更大的 Ox-stress 与 LAMP1 和泛素水平的增加相关，从而将溶酶体在 DNs 中的积累与 Ox-stress 联系起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/77f26c5e94d2/mmcfigs9.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/480475f32b31/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/7b020271f4b5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/6b11b8a38c44/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/c79f5fb8ba5c/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/f39a53e3e19a/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/6cf63277b272/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/e47eec339013/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/52647ceda7d3/mmcfigs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/80807d5a7de3/mmcfigs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/101b5d62c354/mmcfigs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/31bec2f92c03/mmcfigs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/a0cf237f7c6b/mmcfigs5.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/f27b334a1644/mmcfigs7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2826/9440309/77f26c5e94d2/mmcfigs9.jpg

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