Shrivastava Pallavi, Lu Yan, Su Shanchun, Kobayashi Yuichi, Zhao Yuhai, Lien Nathan, Masoud Abdul-Razak, Lukiw Walter J, Hong Song
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, 2020 Gravier St., New Orleans, LA 70112, USA.
Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan.
Biomedicines. 2024 Dec 17;12(12):2865. doi: 10.3390/biomedicines12122865.
(1) Background: Impeded resolution of inflammation contributes substantially to the pathogenesis of Alzheimer's disease (AD); consequently, resolving inflammation is pivotal to the amelioration of AD pathology. This can potentially be achieved by the treatment with specialized pro-resolving lipid mediators (SPMs), which should resolve neuroinflammation in brains. (2) Methods: Here, we report the histological effects of long-term treatment with an SPM, maresin-like 1 (MarL1), on AD pathogenesis in a transgenic 5xFAD mouse model. (3) Results: MarL1 treatment reduced Aβ overload, curbed the loss of neurons in brains especially cholinergic neurons associated with cleaved-caspase-3-associated apoptotic degeneration, reduced microgliosis and the pro-inflammatory M1 polarization of microglia, curbed the AD-associated decline in anti-inflammatory Iba1Arg-1-M2 microglia, inhibited phenotypic switching to pro-inflammatory N1 neutrophils, promoted the blood-brain barrier-associated tight-junction protein claudin-5 and decreased neutrophil leakage in 5xFAD brains, and induced the switch of neutrophils toward the inflammation-resolving N2 phenotype. (4) Conclusions: Long-term administration of MarL1 mitigates AD-related neuropathogenesis in brains by curbing neuroinflammation and neurodegeneration, based on the histological results. These findings provide preclinical leads and mechanistic insights for the development of MarL1 into an effective modality to ameliorate AD pathogenesis.
(1) 背景：炎症消退受阻在很大程度上促成了阿尔茨海默病（AD）的发病机制；因此，解决炎症对于改善AD病理至关重要。这可能通过用专门的促消退脂质介质（SPM）进行治疗来实现，这类介质应能解决大脑中的神经炎症。(2) 方法：在此，我们报告了一种SPM，类maresin 1（MarL1），对转基因5xFAD小鼠模型中AD发病机制的长期治疗的组织学效应。(3) 结果：MarL1治疗减少了Aβ过载，抑制了大脑中神经元的丢失，特别是与裂解的半胱天冬酶-3相关的凋亡性变性相关的胆碱能神经元，减少了小胶质细胞增生以及小胶质细胞的促炎M1极化，抑制了与AD相关的抗炎Iba1Arg-1-M2小胶质细胞的减少，抑制了向促炎N1中性粒细胞的表型转换，促进了血脑屏障相关紧密连接蛋白claudin-5的表达，并减少了5xFAD大脑中的中性粒细胞渗漏，还诱导了中性粒细胞向解决炎症的N2表型转换。(4) 结论：基于组织学结果，长期给予MarL1可通过抑制神经炎症和神经退行性变来减轻大脑中与AD相关的神经病理发生。这些发现为将MarL1开发成改善AD发病机制的有效方式提供了临床前线索和机制性见解。
