Youssef Hossam, Weissmann Carina, Uruk Gokhan, Gatto Rodolfo Gabriel
Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Institute of Physiology, Molecular Biology and Neuroscience, Buenos Aires C1428EGA, Argentina.
Brain Sci. 2025 Jul 3;15(7):716. doi: 10.3390/brainsci15070716.
Transactive response DNA-binding protein of 43 kDa (TDP-43) and tau proteins play critical roles in neurodegenerative diseases, particularly frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). The co-occurrence of TDP-43 and tau pathologies raises questions about their role in disease progression. This review explores the simultaneous presence of tau and TDP-43 co-pathologies, emphasizing their molecular interactions and the resultant neuropathological implications. Additionally, we provide representative examples of their clinical presentations, neuroimaging, and neuropathological findings associated with FTLD-TDP and FTLD-tau, emphasizing the need for a comprehensive understanding of these intertwined pathologies. We analyze various clinical scenarios, including argyrophilic grain disease (AGD), primary age-related tauopathy (PART), and limbic predominant age-related TDP-43 encephalopathy (LATE), to elucidate the complex relationship between these proteinopathies. From the literature, the co-occurrence of tau and TDP-43 is linked to more severe and poorer clinical outcomes compared to isolated pathologies. This review underscores the necessity of considering co-pathologies in the context of FTLD, as they may act as accelerators of cognitive decline. This highlights the importance of integrated approaches in diagnosing and treating neurodegenerative conditions characterized by tau and TDP-43 misfolding. Understanding the interplay between these molecular markers is vital for advancing therapeutic strategies for such disorders.
43 kDa的反式激活反应DNA结合蛋白（TDP-43）和tau蛋白在神经退行性疾病中起关键作用，尤其是额颞叶变性（FTLD）和阿尔茨海默病（AD）。TDP-43和tau病理改变的同时出现引发了关于它们在疾病进展中作用的疑问。本综述探讨了tau和TDP-43共同病理改变的同时存在，强调了它们的分子相互作用以及由此产生的神经病理学意义。此外，我们提供了与FTLD-TDP和FTLD-tau相关的临床表现、神经影像学和神经病理学发现的代表性实例，强调了全面理解这些相互交织的病理改变的必要性。我们分析了各种临床情况，包括嗜银颗粒病（AGD）、原发性年龄相关tau病（PART）和边缘叶为主的年龄相关TDP-43脑病（LATE），以阐明这些蛋白病之间的复杂关系。从文献来看，与单一病理改变相比，tau和TDP-43的同时出现与更严重和更差的临床结局相关。本综述强调了在FTLD背景下考虑共同病理改变的必要性，因为它们可能是认知衰退的加速器。这突出了综合方法在诊断和治疗以tau和TDP-43错误折叠为特征的神经退行性疾病中的重要性。了解这些分子标志物之间的相互作用对于推进此类疾病的治疗策略至关重要。
