Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang District, Taipei, 115, Taiwan.
Department of Anatomy, School of Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Sanmin District, Kaohsiung, 80708, Taiwan.
Nat Commun. 2020 Nov 23;11(1):5950. doi: 10.1038/s41467-020-19786-7.
TDP-43 inclusions are found in many Alzheimer's disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-β (Aβ) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction. TDP-43 significantly enhanced Aβ's ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with Aβ, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aβ in the brain of AD patients. We conclude that TDP-43 inhibits Aβ fibrillization through its interaction with Aβ and exacerbates AD pathology.
TDP-43 包含物存在于许多阿尔茨海默病（AD）患者中，这些患者的疾病进展更快，大脑萎缩程度更大。此前，我们发现全长 TDP-43 形成球形寡聚物并扰乱淀粉样蛋白-β（Aβ）纤维形成。为了阐明 TDP-43 在 AD 中的作用，我们在这里检查了 TDP-43 在 Aβ 聚集中的作用及其在小鼠模型中的毒性作用。我们发现 TDP-43 在初始和寡聚阶段抑制 Aβ 纤维化。在存在含有 N 端结构域的 TDP-43 变体的情况下，Aβ 纤维化被特异性延迟，而 C 端 TDP-43 对 Aβ 相互作用不是必需的。TDP-43 显著增强了 Aβ 损害长时程增强的能力，并且在海马内注射后，导致空间记忆缺陷。在注射到 AD 转基因小鼠后，TDP-43 引起炎症、与 Aβ 相互作用并加剧 AD 样病理学。TDP-43 寡聚体主要与 AD 患者大脑中的细胞内 Aβ 共定位。我们得出结论，TDP-43 通过与 Aβ 的相互作用抑制 Aβ 纤维化，并加剧 AD 病理学。
