Shahidehpour Ryan K, Nelson Peter T, Srinivasan Sukanya, Yu Zhong, Bachstetter Adam D
Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky, USA.
Department of Neuroscience, University of Kentucky, Lexington, Kentucky, USA.
Neuropathology. 2025 Aug;45(4):e70003. doi: 10.1111/neup.70003. Epub 2025 Mar 5.
Mutations in the Integral membrane protein 2B (ITM2B) gene are linked to the development of familial British and Danish dementias, two relatively early-onset dementia disorders known also to be associated with Tau neurofibrillary tangles (NFTs). However, to date, the involvement of ITM2B in limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) remains unclear. To address this question, we used brain samples from the University of Kentucky Alzheimer's Disease Research Center community-based autopsy cohort. We investigated the patterns and co-localizations of ITM2B immunohistochemistry in subiculum, CA1, CA2, CA3 and dentate gyrus of the hippocampus from brains with Alzheimer's disease neuropathologic changes (ADNC), LATE-NC, and comorbid ADNC+LATE-NC, as well as low-pathology controls (n = 4 per disease state). There was frequent co-localization between ITM2B protein and intracellular Tau pathology in ADNC; however, there was a far weaker rate of co-localization between ITM2B and TDP-43 pathology. There also was, as previously described, an association between ITM2B immunostaining and neuritic-appearing amyloid plaques. Additionally, co-localization of intracellular ITM2B pathology with Thioflavin-S in NFTs suggested a potential role for ITM2B in marking neurons undergoing transition from relatively healthy (early NFT-bearing cells) to more severely affected (later NFT-bearing) cellular disease states. This study indicates that ITM2B has a relatively specific pattern of involvement in Tau-related neurodegeneration and in neuritic amyloid plaques, while implying minimal, if any, role for ITM2B in the synergistic relationship between Tau and TDP-43 pathologies.
整合膜蛋白2B（ITM2B）基因的突变与家族性英国和丹麦痴呆症的发展有关，这两种相对早发性痴呆症也已知与 Tau 神经原纤维缠结（NFTs）相关。然而，迄今为止，ITM2B 在以边缘系统为主的年龄相关性 TDP - 43 脑病神经病理变化（LATE - NC）中的作用仍不清楚。为了解决这个问题，我们使用了来自肯塔基大学阿尔茨海默病研究中心基于社区尸检队列的脑样本。我们研究了 ITM2B 免疫组织化学在患有阿尔茨海默病神经病理变化（ADNC）、LATE - NC 和合并 ADNC + LATE - NC 的大脑海马体的下托、CA1、CA2、CA3 和齿状回中的模式和共定位情况，以及低病理对照（每种疾病状态 n = 4）。在 ADNC 中，ITM2B 蛋白与细胞内 Tau 病理之间经常存在共定位；然而，ITM2B 与 TDP - 43 病理之间的共定位率要低得多。如前所述，ITM2B 免疫染色与神经突样淀粉样斑块之间也存在关联。此外，细胞内 ITM2B 病理与硫黄素 - S 在 NFTs 中的共定位表明 ITM2B 在标记从相对健康（早期含 NFT 细胞）向受影响更严重（晚期含 NFT）细胞疾病状态转变的神经元方面可能发挥作用。这项研究表明，ITM2B 在与 Tau 相关的神经退行性变和神经突淀粉样斑块中具有相对特定的参与模式，同时暗示 ITM2B 在 Tau 和 TDP - 43 病理之间的协同关系中作用极小（如果有作用的话）。
