Network proteomics of the Lewy body dementia brain reveals presynaptic signatures distinct from Alzheimer’s disease

IF 14.9 1区 医学 Q1 NEUROSCIENCES Molecular Neurodegeneration Pub Date : 2024-08-06 DOI:10.1186/s13024-024-00749-1
Anantharaman Shantaraman, Eric B. Dammer, Obiadada Ugochukwu, Duc M. Duong, Luming Yin, E. Kathleen Carter, Marla Gearing, Alice Chen-Plotkin, Edward B. Lee, John Q. Trojanowski, David A. Bennett, James J. Lah, Allan I. Levey, Nicholas T. Seyfried, Lenora Higginbotham
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Abstract

Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer’s disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson’s disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or “modules” of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.
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路易体痴呆症大脑网络蛋白质组学揭示了不同于阿尔茨海默病的突触前特征
路易体痴呆(LBD)是由帕金森病痴呆(PDD)和路易体痴呆(DLB)组成的一类疾病,在临床和病理上与阿尔茨海默病(AD)有很大的重叠。鉴定路易体痴呆症病理生理学的独特生物标志物可有效促进其诊断、监测和治疗。我们使用定量质谱法(MS)测量了宾夕法尼亚大学尸检收集的 138 个背外侧前额叶皮层(DLPFC)组织中的 9,000 多种蛋白质,这些组织包括对照组、帕金森病(PD)、PDD 和 DLB 诊断组。然后,我们分析了LBD患者的共表达网络蛋白质改变,在两个独立的LBD数据集中验证了这些疾病特征,并将这些发现与在AD病例网络分析中观察到的结果进行了比较。LBD网络揭示了在PDD和DLB中显著改变的许多共表达蛋白群或 "模块",它们代表了突触、代谢和炎症病理生理学。将经过验证的 LBD 特征与注意力缺失症的特征进行比较,发现了这两种疾病之间的明显差异。值得注意的是,与突触前模块相关的突触核蛋白在 LBD 中升高,而在 AD 中则相对于对照组降低。我们还发现,与神经胶质相关的矩阵组特征在 AD 中持续升高,而在枸杞多糖症中则发生了更多不同程度的改变,最终将枸杞多糖症病例与同时β-淀粉样蛋白沉积负担较低和较高的病例进行了分层。总之,无偏见的网络蛋白质组分析揭示了枸杞多糖大脑额叶皮层的多种病理生理学变化,这些变化不同于AD的改变。这些结果凸显了枸杞多糖脑网络蛋白质组是一种很有前景的生物标志物来源,可以提高临床识别和管理水平。
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来源期刊
Molecular Neurodegeneration
Molecular Neurodegeneration 医学-神经科学
CiteScore
23.00
自引率
4.60%
发文量
78
审稿时长
6-12 weeks
期刊介绍: Molecular Neurodegeneration, an open-access, peer-reviewed journal, comprehensively covers neurodegeneration research at the molecular and cellular levels. Neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and prion diseases, fall under its purview. These disorders, often linked to advanced aging and characterized by varying degrees of dementia, pose a significant public health concern with the growing aging population. Recent strides in understanding the molecular and cellular mechanisms of these neurodegenerative disorders offer valuable insights into their pathogenesis.
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