Department of Imaging and Pathology - Laboratory of Neuropathology, and Leuven Brain Institute, KU-Leuven, O&N IV, Herestraat 49, box 1032, 3000, Leuven, Belgium.
Department of Neurosciences - Laboratory of Cognitive Neurology, KU- Leuven, Leuven, Belgium.
Acta Neuropathol Commun. 2020 Apr 29;8(1):61. doi: 10.1186/s40478-020-00934-5.
The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer's disease (AD) patients, in addition to amyloid-β and τ protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically-defined preclinical AD (p-preAD), 51 neuropathologically-confirmed AD cases and 10 FTLD-TDP cases as positive controls. We observed distinct neuropathological patterns of TDP-43 among AD cases. In 11 neuropathologically-confirmed AD cases we found dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs) and/or neurofibrillary tangle (NFT)-like lesions not only positive for pTDP-43, but also for pTDP-43 phosphorylated at serines 403/404 (pTDP-43) and non-phosphorylated, full-length TDP-43, as seen with antibodies against C-terminal TDP-43 and N-terminal TDP-43. These cases were referred to as AD because full-length TDP-43 was presumably present in the aggregates. FTLD-TDP cases showed a similar molecular TDP-43 pattern. A second pattern, which was not seen in FTLD-TDP, was observed in most of p-preAD, as well as 30 neuropathologically-confirmed AD cases, which mainly exhibited NFTs and NCIs stained with antibodies against TDP-43 phosphorylated at serines 409/410 (pTDP-43, pTDP-43). Because only phosphorylated C-terminal species of TDP-43 could be detected in the lesions we designated these AD cases as AD. Ten AD cases did not contain any TDP-43 pathology and were referred to as AD. The different TDP-43 patterns were associated with clinically typical AD symptoms in 80% of AD cases, 63,6% of AD and 100% of the AD cases. On the other hand, clinical symptoms characteristic for FTD were observed in 36,4% of AD, in 16,6% of the AD, and in none of the AD cases. Our findings provide evidence that TDP-43 aggregates occurring in AD cases vary in their composition, suggesting the distinction of different molecular patterns of TDP-43 pathology ranging from AD to AD and AD with possible impact on their clinical picture, i.e. a higher chance for FTD-like symptoms in AD cases.
认知障碍老年人的大脑中普遍存在多种病理和蛋白质共存的现象。在部分迟发性阿尔茨海默病（AD）患者的边缘脑区，除了淀粉样β和τ蛋白外，还发现了反式激活反应 DNA 结合蛋白（TDP-43）的积累。然而，目前尚不清楚 AD 大脑中的 TDP-43 物种在不同 AD 病例之间以及与具有 TDP-43 包涵体的额颞叶变性病例（FTLD-TDP）相比，其组成是否存在差异。此外，尚不清楚 AD 中的 TDP-43 病理学是否与额颞痴呆（FTD）谱的症状有关。在这项研究中，我们使用了五种针对不同磷酸化（pTDP-43）和非磷酸化 TDP-43 表位的不同磷酸化 TDP-43 抗体，研究了 TDP-43 病变的分子模式。我们分析了 97 例尸检病例，包括 20 名非痴呆个体、16 名认知正常的病理性预临床 AD（p-preAD）、51 名神经病理学确诊的 AD 病例和 10 例 FTLD-TDP 病例作为阳性对照。我们观察到 AD 病例中存在不同的 TDP-43 病理模式。在 11 例神经病理学确诊的 AD 病例中，我们发现了不仅对 pTDP-43 而且对丝氨酸 403/404 磷酸化的 pTDP-43（pTDP-43）和非磷酸化全长 TDP-43 呈阳性的神经突萎缩（DN）、神经元细胞质包涵体（NCIs）和/或神经原纤维缠结（NFT）样病变，这些病变使用针对 C 端 TDP-43 和 N 端 TDP-43 的抗体可以看到。这些病例被称为 AD，因为全长 TDP-43 可能存在于聚集体中。FTLD-TDP 病例表现出类似的 TDP-43 分子模式。在大多数 p-preAD 以及 30 例神经病理学确诊的 AD 病例中观察到另一种模式，这种模式在 FTLD-TDP 中未见，主要表现为用针对 TDP-43 丝氨酸 409/410 磷酸化的抗体（pTDP-43、pTDP-43）染色的 NFT 和 NCIs。由于仅在病变中检测到磷酸化的 C 端 TDP-43 物种，因此我们将这些 AD 病例指定为 AD。10 例 AD 病例不含有任何 TDP-43 病理学，被称为 AD。不同的 TDP-43 模式与 80%的 AD 病例、63.6%的 AD 和 100%的 AD 病例的典型 AD 症状相关。另一方面，在 36.4%的 AD、16.6%的 AD 和没有 AD 病例中观察到与 FTD 特征相关的临床症状。我们的研究结果表明，AD 病例中存在的 TDP-43 聚集体在组成上存在差异，这表明 TDP-43 病理学存在不同的分子模式，从 AD 到 AD 和 AD 都存在，这可能对其临床症状产生影响，即 AD 病例出现 FTD 样症状的可能性更高。
