Canal-Garcia Anna, Branca Rui M, Francis Paul T, Ballard Clive, Winblad Bengt, Lehtiö Janne, Nilsson Per, Aarsland Dag, Pereira Joana B, Bereczki Erika
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Department of Oncology-Pathology, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
Alzheimers Dement. 2025 Jan;21(1):e14375. doi: 10.1002/alz.14375. Epub 2024 Dec 23.
We aimed to identify unique proteomic signatures of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD).
We conducted a comparative proteomic analysis of 33 post mortem brains from AD, DLB, and PDD individuals without dementia focusing on prefrontal, cingulate, and parietal cortices, using weighted gene co-expression network analyses with differential enrichment analysis.
Network modules revealed hub proteins common to all dementias. Lewy body dementias differed from AD by reduced levels of the autophagy protein p62 (SQSTM1), whereas DLB was distinguished from both AD and PDD by altered TRIM33 and cysteine/glutamate transporter (SLC7A11) across brain regions. An increase in mitochondrial and synaptic proteins was related to better cognition whereas enrichment in the extracellular matrix, complement system, and autophagy proteins was associated with greater cognitive impairment.
Our study offers valuable insights into the network-based biomarker characterization of molecular signatures of AD, DLB, and PDD.
Reduced levels of the autophagy protein p62 (SQSTM1) differentiated Lewy body dementias from Alzheimer's disease (AD) across multiple brain regions. Dementia with Lewy bodies (DLB) was distinguished from both AD and Parkinson's disease dementia (PDD) by altered TRIM33 and cysteine/glutamate transporter (SLC7A11) levels across brain regions. Key mitochondrial oxidative phosphorylation proteins (e.g., COX7A2, TOMM40L, NDUFV1), and synaptic proteins (e.g., GABRB3, GABRB2, GLUA3, GLUA4, SNAP47, dynamin1) were more abundant in preserved cognitive states. Extracellular matrix proteins and members of the complement system (decorin, biglycan, C4A, C4B) showed a strong positive correlation with cognitive decline.
我们旨在识别阿尔茨海默病（AD）、路易体痴呆（DLB）和帕金森病痴呆（PDD）独特的蛋白质组学特征。
我们对33例来自AD、DLB和无痴呆的PDD个体的死后大脑进行了比较蛋白质组学分析，重点关注前额叶、扣带回和顶叶皮质，采用加权基因共表达网络分析和差异富集分析。
网络模块揭示了所有痴呆症共有的枢纽蛋白。路易体痴呆与AD的不同之处在于自噬蛋白p62（SQSTM1）水平降低，而DLB与AD和PDD的区别在于大脑各区域TRIM33和半胱氨酸/谷氨酸转运体（SLC7A11）的改变。线粒体和突触蛋白的增加与较好的认知功能相关，而细胞外基质、补体系统和自噬蛋白的富集与更严重的认知障碍相关。
我们的研究为基于网络的AD、DLB和PDD分子特征生物标志物表征提供了有价值的见解。
自噬蛋白p62（SQSTM1）水平降低在多个脑区将路易体痴呆与阿尔茨海默病（AD）区分开来。路易体痴呆（DLB）与AD和帕金森病痴呆（PDD）的区别在于大脑各区域TRIM33和半胱氨酸/谷氨酸转运体（SLC7A11）水平的改变。关键的线粒体氧化磷酸化蛋白（如COX7A2、TOMM40L、NDUFV1）和突触蛋白（如GABRB3、GABRB2、GLUA3、GLUA4、SNAP47、动力蛋白1）在认知状态保留时更为丰富。细胞外基质蛋白和补体系统成员（核心蛋白聚糖、双糖链蛋白聚糖、C4A、C4B）与认知衰退呈强正相关。
