<br>5xFAD 小鼠的多蛋白质组学分析揭示了早期阿尔茨海默病的新分子特征,Aging Cell

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5xFAD 小鼠的多蛋白质组学分析揭示了早期阿尔茨海默病的新分子特征
Aging Cell ( IF 8.0 ) Pub Date : 2024-03-04 , DOI: 10.1111/acel.14137
Seulah Lee ₁ , Kuk-In Jang ₂ , Hagyeong Lee ₁ , Yeon Suk Jo _{1,

3} , Dayoung Kwon ₁ , Geuna Park ₁ , Sungwon Bae ₁ , Yang Woo Kwon ₁ , Jin-Hyeok Jang ₃ , Yong-Seok Oh ₃ , Chany Lee ₂ , Jong Hyuk Yoon ₁

Affiliation

阿尔茨海默病的早期诊断至关重要，因为治疗效果仅限于早期阶段。然而，由于临床检查和淀粉样斑块成像的局限性，目前的诊断方法仅限于疾病发展的中后期。因此，本研究旨在鉴定与阿尔茨海默病相关的分子特征，包括血浆细胞外囊泡生物标志物蛋白，以帮助早期诊断。使用定量蛋白质组学分析 3 个月和 6 个月大的 5xFAD 小鼠的海马体、皮质和血浆细胞外囊泡。随后进行生物信息学和生化分析，比较不同大脑区域和年龄组的野生型小鼠和 5xFAD 小鼠之间的分子特征，以阐明疾病病理学。 3 个月和 6 个月大的小鼠的海马和皮质蛋白质组中存在显着改变的蛋白质的独特特征。与其他蛋白质组相比，血浆细胞外囊泡蛋白质组表现出独特的信息特征。此外，海马体和皮质之间的几种经典途径（包括磷脂酰肌醇 3-激酶/蛋白激酶 B 信号传导）的调节也不同。使用来自不同阶段的患者的血浆细胞外囊泡鉴定并验证了十二种用于检测早期阿尔茨海默病的潜在生物标志物。最后，使用机器学习模型，约 79% 的患者选择整合素 α-IIb、肌酸激酶 M 型、细丝蛋白 C、谷氨酰胺 γ-谷氨酰转移酶 2 和溶酶体 α-甘露糖苷酶作为健康个体和早期阿尔茨海默病患者的区分生物标志物准确性。我们的研究发现了与阿尔茨海默病进展相关的新的早期分子特征，从而为其发病机制提供了新的见解。

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Multi-proteomic analyses of 5xFAD mice reveal new molecular signatures of early-stage Alzheimer's disease

An early diagnosis of Alzheimer's disease is crucial as treatment efficacy is limited to the early stages. However, the current diagnostic methods are limited to mid or later stages of disease development owing to the limitations of clinical examinations and amyloid plaque imaging. Therefore, this study aimed to identify molecular signatures including blood plasma extracellular vesicle biomarker proteins associated with Alzheimer's disease to aid early-stage diagnosis. The hippocampus, cortex, and blood plasma extracellular vesicles of 3- and 6-month-old 5xFAD mice were analyzed using quantitative proteomics. Subsequent bioinformatics and biochemical analyses were performed to compare the molecular signatures between wild type and 5xFAD mice across different brain regions and age groups to elucidate disease pathology. There was a unique signature of significantly altered proteins in the hippocampal and cortical proteomes of 3- and 6-month-old mice. The plasma extracellular vesicle proteomes exhibited distinct informatic features compared with the other proteomes. Furthermore, the regulation of several canonical pathways (including phosphatidylinositol 3-kinase/protein kinase B signaling) differed between the hippocampus and cortex. Twelve potential biomarkers for the detection of early-stage Alzheimer's disease were identified and validated using plasma extracellular vesicles from stage-divided patients. Finally, integrin α-IIb, creatine kinase M-type, filamin C, glutamine γ-glutamyltransferase 2, and lysosomal α-mannosidase were selected as distinguishing biomarkers for healthy individuals and early-stage Alzheimer's disease patients using machine learning modeling with approximately 79% accuracy. Our study identified novel early-stage molecular signatures associated with the progression of Alzheimer's disease, thereby providing novel insights into its pathogenesis.

更新日期：2024-03-04

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