Spinal cord and brain injury research center, Sander-Brown Center on Aging, Department of Neuroscience, University of Kentucky, 741 S. Limestone St, Lexington, KY, 40536, USA.
Department of Neuroscience, University of Kentucky, Lexington, KY, USA.
Acta Neuropathol Commun. 2024 Jul 12;12(1):114. doi: 10.1186/s40478-024-01826-8.
TAR DNA-Binding Protein 43 (TDP-43) pathological inclusions are a distinctive feature in dozens of neurodegenerative pathologies, including limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Prior investigations identified vascular-associated TDP-43-positive micro-lesions, known as "Lin bodies," located on or near the brain capillaries of some individuals with LATE-NC. This study aimed to investigate the relationship between the accumulation of Lin bodies and glial cells in LATE-NC and the potential co-localization with ferritin, a protein associated with iron storage. Using multiplexed immunohistochemistry and digital pathology tools, we conducted pathological analyses to investigate the relationship between Lin bodies and glial markers (GFAP for astrocytes, IBA1 for microglia) and ferritin. Analyses were conducted on post-mortem brain tissues collected from individuals with pathologically confirmed Alzheimer's disease neuropathological changes (ADNC) and LATE-NC.
As shown previously, there was a robust association between Lin bodies and GFAP-positive astrocyte processes. Moreover, we also observed Lin bodies frequently co-localizing with ferritin, suggesting a potential link to compromised vascular integrity. Subsequent analyses demonstrated increased astrocytosis near Lin body-positive vessels compared to those without Lin bodies, particularly in ADNC cases. These results suggest that the accumulation of Lin bodies may elicit an increased glial response, particularly among astrocytes, possibly related to impaired vascular integrity.
Lin bodies are associated with a local reactive glial response. The strong association of Lin bodies with ferritin suggests that the loss of vascular integrity may be either a cause or a consequence of the pTDP-43 pathology. The reactive glia surrounding the affected vessels could further compromise vascular function.
TAR DNA 结合蛋白 43（TDP-43）病理性包涵体是数十种神经退行性病变的一个显著特征，包括边缘为主的与年龄相关的 TDP-43 脑质病神经病理改变（LATE-NC）。先前的研究发现了与血管相关的 TDP-43 阳性微病变，称为“Lin 体”，位于 LATE-NC 一些个体的脑毛细血管上或附近。本研究旨在探讨 LATE-NC 中 Lin 体与神经胶质细胞的堆积之间的关系，以及与铁储存相关的蛋白 ferritin 的潜在共定位关系。我们使用多重免疫组织化学和数字病理学工具进行病理学分析，以研究 Lin 体与神经胶质标志物（星形胶质细胞的 GFAP、小胶质细胞的 IBA1）和 ferritin 之间的关系。分析是在死后脑组织中进行的，这些脑组织来自病理证实的阿尔茨海默病神经病理改变（ADNC）和 LATE-NC 个体。
如前所述，Lin 体与 GFAP 阳性星形胶质细胞突起之间存在很强的关联。此外，我们还观察到 Lin 体经常与 ferritin 共定位，这表明与血管完整性受损有关。后续分析表明，与没有 Lin 体的血管相比，Lin 体阳性血管附近的星形胶质细胞增生增加，尤其是在 ADNC 病例中。这些结果表明，Lin 体的堆积可能引发更强的神经胶质反应，特别是星形胶质细胞，这可能与血管完整性受损有关。
Lin 体与局部反应性神经胶质有关。Lin 体与 ferritin 的强关联表明，血管完整性的丧失可能是 pTDP-43 病理学的原因或结果。受影响血管周围的反应性胶质细胞可能进一步损害血管功能。
