Barahona Rocio A, Kwang Nellie E, Kono-Soosaipillai Aashna R, Rubio Salgado Giovanna, Tran Kristine M, Lu Yueh-Hao, Reddy Siddharth, da Cunha Celia, Velazquez-Rivera Eric, Crapser Joshua D, Xu Xiangmin, Hohsfield Lindsay A, Green Kim N
Department of Neurobiology and Behavior, Charlie Dunlop School of Biological Sciences, University of California, Irvine, Irvine, CA 92697, USA.
Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
Cell Rep. 2025 Aug 26;44(8):116064. doi: 10.1016/j.celrep.2025.116064. Epub 2025 Jul 31.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles. Recent evidence implicates extracellular matrix (ECM) dysfunction in disease pathogenesis, including extensive loss of perineuronal nets (PNNs). PNNs are neuron-ensheathing condensed ECM structures composed of chondroitin sulfate proteoglycans, including the main constituent aggrecan (ACAN). To explore the role of PNNs in AD, we utilize the 5xFAD model and genetically target Acan in Nestin-expressing cells, resulting in loss of ACAN and ablation of the PNN structure. In 5xFAD mice, ACAN cKO results in increased plaque deposition, reduced plaque sphericity, and impaired microglia-plaque association. Single-cell spatial transcriptomics identifies an enhanced disease-associated microglia (DAM) phenotype in 5xFAD ACAN cKO mice, which is accompanied by decreased dystrophic neurite formation. Collectively, our data suggest that PNNs may play a crucial role in mediating the microglial response to plaques.
阿尔茨海默病（AD）是一种以淀粉样斑块和神经原纤维缠结为特征的神经退行性疾病。最近的证据表明细胞外基质（ECM）功能障碍参与了疾病的发病机制，包括神经周网（PNN）的广泛丧失。PNN是由硫酸软骨素蛋白聚糖组成的包裹神经元的浓缩ECM结构，包括主要成分聚集蛋白聚糖（ACAN）。为了探究PNN在AD中的作用，我们利用5xFAD模型并在表达巢蛋白的细胞中对Acan进行基因靶向，导致ACAN缺失和PNN结构消融。在5xFAD小鼠中，ACAN条件性敲除（cKO）导致斑块沉积增加、斑块球形度降低以及小胶质细胞与斑块的关联受损。单细胞空间转录组学确定了5xFAD ACAN cKO小鼠中增强的疾病相关小胶质细胞（DAM）表型，同时伴有营养不良性神经突形成减少。总体而言，我们的数据表明PNN可能在介导小胶质细胞对斑块的反应中起关键作用。
