Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Neuropathology. 2024 Apr;44(2):115-125. doi: 10.1111/neup.12938. Epub 2023 Jul 31.
Transactive response DNA-binding protein 43 (TDP-43) pathological inclusions are found in frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer's disease (AD-TDP). While clinically different, TDP-43 inclusions in FTLD-TDP and AD can have similar morphological characteristics. However, TDP-43 colocalizing with tau and forming "apple-bite" or "flame-shaped" neuronal cytoplasmic inclusions (NCI) are only found in AD-TDP. Here, we describe a case with AD and neuritic plaque-associated TDP-43. The patient was a 96-year-old right-handed Caucasian woman who had developed a slowly progressive amnestic syndrome compatible with typical AD at age 80. Genetic testing revealed APOE ε3/ε4, GRN r5848 CT, and MAPT H1/H2 genotype. Consistent with the old age at onset and long disease duration, limbic-predominant AD was found at autopsy, with high hippocampal yet low cortical neurofibrillary tangle (NFT) counts. Hippocampal and amygdala sclerosis were present. Immunohistochemistry for phospho-TDP-43 showed NCIs, dystrophic neurites, and rare neuronal intranuclear inclusions consistent with FTLD-TDP type A, as well as tau NFT-associated TDP-43 inclusions. These were frequent in the amygdala, entorhinal cortex, hippocampus, occipitotemporal gyrus, and inferior temporal gyrus but sparse in the mid-frontal cortex. Additionally, there were TDP-43-immunoreactive inclusions forming plaque-like structures in the molecular layer of the dentate fascia of the hippocampus. The presence of neuritic plaques in the same region was confirmed using thioflavin-S fluorescent microscopy and immunohistochemistry for phospho-tau. Double labeling immunofluorescence showed colocalization of TDP-43 and tau within neuritic plaques. Other pathologies included mild Lewy body pathology predominantly affecting the amygdala and olfactory bulb, aging-related tau astrogliopathy, and mixed small vessel disease (arteriolosclerosis and amyloid angiopathy) with several cortical microinfarcts. In conclusion, we have identified TDP-43 colocalizing with tau in neuritic plaques in AD, which expands the association of TDP-43 and tau in AD beyond NFTs. The clinical correlate of this plaque-associated TDP-43 appears to be a slowly progressive amnestic syndrome.
转译反应 DNA 结合蛋白 43（TDP-43）病理学包含物存在于额颞叶变性（FTLD-TDP）和阿尔茨海默病（AD-TDP）中。虽然在临床上不同，但 FTLD-TDP 和 AD 中的 TDP-43 包含物可能具有相似的形态特征。然而，仅在 AD-TDP 中才发现 TDP-43 与 tau 共定位并形成“苹果咬”或“火焰形”神经元细胞质包含物（NCI）。在这里，我们描述了一例 AD 患者和神经炎斑块相关 TDP-43。患者为 96 岁的右利手白种女性，80 岁时出现缓慢进展的健忘综合征，符合典型 AD。基因检测显示 APOE ε3/ε4、GRN r5848 CT 和 MAPT H1/H2 基因型。尸检发现，与发病年龄较大和疾病持续时间较长一致，存在边缘优势 AD，海马神经纤维缠结（NFT）计数高，皮质 NFT 计数低。存在海马和杏仁核硬化。磷酸化 TDP-43 的免疫组织化学显示 NCI、营养不良的神经突和罕见的神经元核内包含物，符合 FTLD-TDP 型 A，以及与 tau NFT 相关的 TDP-43 包含物。这些在杏仁核、内嗅皮质、海马、枕颞叶和下颞叶中很常见，但在中额叶皮质中很少见。此外，在海马齿状回 fascia 的分子层中还存在形成斑块样结构的 TDP-43 免疫反应性包含物。通过硫黄素-S 荧光显微镜和磷酸化 tau 的免疫组织化学证实同一区域存在神经炎斑块。双标记免疫荧光显示 TDP-43 和 tau 在神经炎斑块内共定位。其他病理学包括主要影响杏仁核和嗅球的轻度路易体病理学、与年龄相关的 tau 星形胶质病以及伴有几个皮质微梗死的混合小血管疾病（小动脉硬化和血管淀粉样变性）。总之，我们已经在 AD 的神经炎斑块中发现了 TDP-43 与 tau 共定位，这扩展了 AD 中 TDP-43 和 tau 的关联超出了 NFT。这种斑块相关 TDP-43 的临床相关性似乎是一种缓慢进展的健忘综合征。
