Neurim Pharmaceuticals Ltd, Tel-Aviv, Israel.
The Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
J Alzheimers Dis. 2017;58(4):1137-1149. doi: 10.3233/JAD-161245.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, deposition of amyloid-β (Aβ) plaques, intracellular neurofibrillary tangles, and neuronal cell death. Neuroinflammation is commonly believed to participate in AD pathogenesis. CD44 is an inflammation-related gene encoding a widely-distributed family of alternatively spliced cell surface glycoproteins that have been implicated in inflammation, metastases, and inflammation-linked neuronal injuries. Here we investigated the expression patterns of CD44S (which does not contain any alternative exon) and CD44 splice variants in postmortem hippocampal samples from AD patients and matched non-AD controls. The expression of CD44S and CD44 splice variants CD44V3, CD44V6, and CD44V10 was significantly higher in AD patients compared to non-AD controls. Immunohistochemistry of human hippocampal sections revealed that CD44S differentially localized to neuritic plaques and astrocytes, whereas CD44V3, CD44V6, and CD44V10 expression was mostly neuronal. Consistent with these findings, we found that the expression of CD44V6 and CD44V10 was induced by Aβ peptide in neuroblastoma cells and primary neurons. Furthermore, in loss of function studies we found that both CD44V10-specific siRNA and CD44V10 antibody protected neuronal cells from Aβ-induced toxicity, suggesting a causal relationship between CD44V10 and neuronal cell death. These data indicate that certain CD44 splice variants contribute to AD pathology and that CD44V10 inhibition may serve as a new neuroprotective treatment strategy for this disease.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征是认知功能障碍、淀粉样β（Aβ）斑块沉积、细胞内神经原纤维缠结和神经元细胞死亡。普遍认为神经炎症参与 AD 的发病机制。CD44 是一种与炎症相关的基因，编码广泛分布的细胞表面糖蛋白家族，该家族与炎症、转移和与炎症相关的神经元损伤有关。在这里，我们研究了 AD 患者和匹配的非 AD 对照死后海马组织中 CD44S（不包含任何替代外显子）和 CD44 剪接变体的表达模式。与非 AD 对照组相比，AD 患者的 CD44S 和 CD44 剪接变体 CD44V3、CD44V6 和 CD44V10 的表达显著升高。对人类海马切片的免疫组织化学研究表明，CD44S 差异定位于神经原纤维缠结和星形胶质细胞，而 CD44V3、CD44V6 和 CD44V10 的表达主要是神经元。与这些发现一致，我们发现 Aβ 肽可诱导神经母细胞瘤细胞和原代神经元中 CD44V6 和 CD44V10 的表达。此外，在功能丧失研究中，我们发现 CD44V10 特异性 siRNA 和 CD44V10 抗体均可保护神经元细胞免受 Aβ 诱导的毒性，表明 CD44V10 与神经元细胞死亡之间存在因果关系。这些数据表明，某些 CD44 剪接变体有助于 AD 病理学，CD44V10 抑制可能成为该疾病新的神经保护治疗策略。
