Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Synapse. 2023 Jul;77(4):e22268. doi: 10.1002/syn.22268. Epub 2023 Apr 13.
Vascular dementia (VaD) is a prevalent cause of dementia after Alzheimer's disease. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUCMSC-Evs) are critical for VaD treatment. We explored the mechanism of hUCMSC-Evs in VaD. VaD rat model was established by bilateral common carotid artery ligation and hUCMSC-Evs were extracted. VaD rats were injected with Evs through the tail vein. Rat neurological scores, neural behaviors, memory and learning abilities, brain tissue pathological changes, and neurological impairment were evaluated by Zea-Longa method, Morris water maze tests, HE staining, and ELISA (through acetylcholine [ACH] and dopamine [DA] assessment). Microglia M1/M2 polarization was detected by immunofluorescence staining. Pro-/anti-inflammatory factor levels in brain tissue homogenate, oxidative stress-related indicators, and p-PI3K, PI3K, p-AKT, AKT, and Nrf2 protein levels were determined by ELISA, kits, and Western blot. VaD rats were jointly treated with PI3K phosphorylation inhibitor Ly294002 and hUCMSC-Evs. VaD rats manifested increased neurological function injury scores, decreased cognitive function and learning ability, abnormal brain structure, obvious inflammatory infiltration, diminished ACH and DA levels, increased microglial cells and M1-polarized cells, M1/M2 polarization ratio, inflammation, and oxidative stress. hUCMSC-Evs alleviated the neurological damage of VaD rats, inhibited M1 polarization, inflammation, and oxidative stress of microglial cells in brain tissues of VaD rats, and activated the PI3K/AKT/Nrf2 pathway. Ly294002 partially averted the effects of hUCMSC-Evs on microglial polarization, inflammation, and oxidative stress. Briefly, hUCMSC-Evs activated the PI3K/AKT/Nrf2 pathway and inhibited microglial M1 polarization, inflammation, and oxidative stress, thus protecting VaD rat nerve functions.
血管性痴呆（VaD）是继阿尔茨海默病之后最常见的痴呆症病因。人脐带间充质干细胞衍生的细胞外囊泡（hUCMSC-Evs）对 VaD 治疗至关重要。我们探讨了 hUCMSC-Evs 在 VaD 中的作用机制。通过双侧颈总动脉结扎建立 VaD 大鼠模型，并提取 hUCMSC-Evs。通过尾静脉向 VaD 大鼠注射 Evs。采用 Zea-Longa 法、Morris 水迷宫试验、HE 染色和 ELISA（通过乙酰胆碱[ACH]和多巴胺[DA]评估）评估大鼠神经评分、神经行为、记忆和学习能力、脑组织病理变化和神经损伤。通过免疫荧光染色检测小胶质细胞 M1/M2 极化。通过 ELISA、试剂盒和 Western blot 测定脑组织匀浆中促炎/抗炎因子水平、氧化应激相关指标以及 p-PI3K、PI3K、p-AKT、AKT 和 Nrf2 蛋白水平。联合使用 PI3K 磷酸化抑制剂 Ly294002 和 hUCMSC-Evs 共同治疗 VaD 大鼠。VaD 大鼠表现出增加的神经功能损伤评分、降低的认知功能和学习能力、异常的大脑结构、明显的炎症浸润、减少的 ACH 和 DA 水平、增加的小胶质细胞和 M1 极化细胞、M1/M2 极化比、炎症和氧化应激。hUCMSC-Evs 减轻 VaD 大鼠的神经损伤，抑制 VaD 大鼠脑组织中小胶质细胞的 M1 极化、炎症和氧化应激，激活 PI3K/AKT/Nrf2 通路。Ly294002 部分逆转了 hUCMSC-Evs 对小胶质细胞极化、炎症和氧化应激的作用。简而言之，hUCMSC-Evs 通过激活 PI3K/AKT/Nrf2 通路，抑制小胶质细胞 M1 极化、炎症和氧化应激，从而保护 VaD 大鼠的神经功能。
