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Abstract：
BACKGROUND: Alzheimer\'s disease (AD) is a neurodegenerative disease characterized by Aβ plaques and neurofibrillary tangles. Chronic inflammation and synaptic dysfunction lead to disease progression and cognitive decline. Small extracellular vesicles (sEVs) are implicated in AD progression by facilitating the spread of pathological proteins and inflammatory cytokines. This study investigates synaptic dysfunction and neuroinflammation protein markers in plasma-derived sEVs (PsEVs), their association with Amyloid-β and tau pathologies, and their correlation with AD progression.
METHODS: A total of 90 [AD = 35, mild cognitive impairment (MCI) = 25, and healthy age-matched controls (AMC) = 30] participants were recruited. PsEVs were isolated using a chemical precipitation method, and their morphology was characterized by transmission electron microscopy. Using nanoparticle tracking analysis, the size and concentration of PsEVs were determined. Antibody-based validation of PsEVs was done using CD63, CD81, TSG101, and L1CAM antibodies. Synaptic dysfunction and neuroinflammation were evaluated with synaptophysin, TNF-α, IL-1β, and GFAP antibodies. AD-specific markers, amyloid-β (1-42), and p-Tau were examined within PsEVs using Western blot and ELISA.
RESULTS: Our findings reveal higher concentrations of PsEVs in AD and MCI compared to AMC (p < 0.0001). Amyloid-β (1-42) expression within PsEVs is significantly elevated in MCI and AD compared to AMC. We could also differentiate between the amyloid-β (1-42) expression in AD and MCI. Similarly, PsEVs-derived p-Tau exhibited elevated expression in MCI compared with AMC, which is further increased in AD. Synaptophysin exhibited downregulated expression in PsEVs from MCI to AD (p = 0.047) compared to AMC, whereas IL-1β, TNF-α, and GFAP showed increased expression in MCI and AD compared to AMC. The correlation between the neuropsychological tests and PsEVs-derived proteins (which included markers for synaptic integrity, neuroinflammation, and disease pathology) was also performed in our study. The increased number of PsEVs correlates with disease pathological markers, synaptic dysfunction, and neuroinflammation.
CONCLUSIONS: Elevated PsEVs, upregulated amyloid-β (1-42), and p-Tau expression show high diagnostic accuracy in AD. The downregulated synaptophysin expression and upregulated neuroinflammatory markers in AD and MCI patients suggest potential synaptic degeneration and neuroinflammation. These findings support the potential of PsEV-associated biomarkers for AD diagnosis and highlight synaptic dysfunction and neuroinflammation in disease progression.
METHODS: A total of 90 [AD = 35, mild cognitive impairment (MCI) = 25, and healthy age-matched controls (AMC) = 30] participants were recruited. PsEVs were isolated using a chemical precipitation method, and their morphology was characterized by transmission electron microscopy. Using nanoparticle tracking analysis, the size and concentration of PsEVs were determined. Antibody-based validation of PsEVs was done using CD63, CD81, TSG101, and L1CAM antibodies. Synaptic dysfunction and neuroinflammation were evaluated with synaptophysin, TNF-α, IL-1β, and GFAP antibodies. AD-specific markers, amyloid-β (1-42), and p-Tau were examined within PsEVs using Western blot and ELISA.
RESULTS: Our findings reveal higher concentrations of PsEVs in AD and MCI compared to AMC (p < 0.0001). Amyloid-β (1-42) expression within PsEVs is significantly elevated in MCI and AD compared to AMC. We could also differentiate between the amyloid-β (1-42) expression in AD and MCI. Similarly, PsEVs-derived p-Tau exhibited elevated expression in MCI compared with AMC, which is further increased in AD. Synaptophysin exhibited downregulated expression in PsEVs from MCI to AD (p = 0.047) compared to AMC, whereas IL-1β, TNF-α, and GFAP showed increased expression in MCI and AD compared to AMC. The correlation between the neuropsychological tests and PsEVs-derived proteins (which included markers for synaptic integrity, neuroinflammation, and disease pathology) was also performed in our study. The increased number of PsEVs correlates with disease pathological markers, synaptic dysfunction, and neuroinflammation.
CONCLUSIONS: Elevated PsEVs, upregulated amyloid-β (1-42), and p-Tau expression show high diagnostic accuracy in AD. The downregulated synaptophysin expression and upregulated neuroinflammatory markers in AD and MCI patients suggest potential synaptic degeneration and neuroinflammation. These findings support the potential of PsEV-associated biomarkers for AD diagnosis and highlight synaptic dysfunction and neuroinflammation in disease progression.
摘要：
背景：阿尔茨海默病（AD）是一种以Aβ斑块和神经原纤维缠结为特征的神经退行性疾病。慢性炎症和突触功能障碍导致疾病进展和认知下降。小细胞外囊泡(sEV)通过促进病理蛋白和炎性细胞因子的扩散而参与AD进展。这项研究调查了血浆来源的sEV（PsEV）中的突触功能障碍和神经炎症蛋白标志物，它们与淀粉样蛋白-β和tau病理有关，以及它们与AD进展的相关性。
方法：共招募90名[AD=35，轻度认知障碍（MCI）=25，健康年龄匹配对照（AMC）=30]参与者。PsEV使用化学沉淀法分离，并通过透射电子显微镜对其形态进行了表征。使用纳米粒子跟踪分析，确定PsEV的大小和浓度。使用CD63、CD81、TSG101和L1CAM抗体对PsEV进行基于抗体的验证。用突触素评估突触功能障碍和神经炎症，TNF-α,IL-1β,和GFAP抗体。AD特异性标志物,淀粉样蛋白-β（1-42），使用蛋白质印迹和ELISA检查PsEV内的p-Tau。
结果：我们的发现表明，与AMC相比，AD和MCI中的PsEV浓度更高（p<0.0001）。与AMC相比,在MCI和AD中PsEV内的淀粉样蛋白-β(1-42)表达显著升高。我们还可以区分AD和MCI中淀粉样蛋白-β(1-42)的表达。同样，与AMC相比，PsEV衍生的p-Tau在MCI中表达升高，在AD中进一步增加。与AMC相比，突触素在从MCI到AD的PsEV中表达下调（p=0.047），而IL-1β，TNF-α,与AMC相比，GFAP在MCI和AD中的表达增加。神经心理学测试与PsEVs衍生蛋白（包括突触完整性标记，神经炎症，和疾病病理学）也在我们的研究中进行。PsEV数量的增加与疾病病理标志物相关，突触功能障碍,和神经炎症。
结论：PsEV升高，上调的淀粉样蛋白-β（1-42），和p-Tau表达在AD中显示出较高的诊断准确性。AD和MCI患者中突触素表达下调和神经炎症标志物上调提示潜在的突触变性和神经炎症。这些发现支持PsEV相关生物标志物用于AD诊断的潜力，并突出疾病进展中的突触功能障碍和神经炎症。
方法：共招募90名[AD=35，轻度认知障碍（MCI）=25，健康年龄匹配对照（AMC）=30]参与者。PsEV使用化学沉淀法分离，并通过透射电子显微镜对其形态进行了表征。使用纳米粒子跟踪分析，确定PsEV的大小和浓度。使用CD63、CD81、TSG101和L1CAM抗体对PsEV进行基于抗体的验证。用突触素评估突触功能障碍和神经炎症，TNF-α,IL-1β,和GFAP抗体。AD特异性标志物,淀粉样蛋白-β（1-42），使用蛋白质印迹和ELISA检查PsEV内的p-Tau。
结果：我们的发现表明，与AMC相比，AD和MCI中的PsEV浓度更高（p<0.0001）。与AMC相比,在MCI和AD中PsEV内的淀粉样蛋白-β(1-42)表达显著升高。我们还可以区分AD和MCI中淀粉样蛋白-β(1-42)的表达。同样，与AMC相比，PsEV衍生的p-Tau在MCI中表达升高，在AD中进一步增加。与AMC相比，突触素在从MCI到AD的PsEV中表达下调（p=0.047），而IL-1β，TNF-α,与AMC相比，GFAP在MCI和AD中的表达增加。神经心理学测试与PsEVs衍生蛋白（包括突触完整性标记，神经炎症，和疾病病理学）也在我们的研究中进行。PsEV数量的增加与疾病病理标志物相关，突触功能障碍,和神经炎症。
结论：PsEV升高，上调的淀粉样蛋白-β（1-42），和p-Tau表达在AD中显示出较高的诊断准确性。AD和MCI患者中突触素表达下调和神经炎症标志物上调提示潜在的突触变性和神经炎症。这些发现支持PsEV相关生物标志物用于AD诊断的潜力，并突出疾病进展中的突触功能障碍和神经炎症。
