Lo Cascio Filippa, Park Suhyeorn, Sengupta Urmi, Puangmalai Nicha, Bhatt Nemil, Shchankin Nikita, Jerez Cynthia, Moreno Naomi, Bittar Alice, Xavier Rhea, Zhao Yingxin, Wang Cankun, Fu Hongjun, Ma Qin, Montalbano Mauro, Kayed Rakez
Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA.
Departments of Neurology, Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, USA.
Commun Biol. 2025 Jan 15;8(1):53. doi: 10.1038/s42003-025-07499-w.
Aggregation of microtubule-associated tau protein is a distinct hallmark of several neurodegenerative disorders such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP). Tau oligomers are suggested to be the primary neurotoxic species that initiate aggregation and propagate prion-like structures. Furthermore, different diseases are shown to have distinct structural characteristics of aggregated tau, denoted as polymorphs. Here, we investigate the structural and functional differences of amplified brain-derived tau oligomers (aBDTOs) from AD, DLB, and PSP. Our results indicate that the aBDTOs possess different structural and morphological features that impact neuronal function, gene regulation, and ultimately disease progression. The distinct tau oligomeric polymorphs may thus contribute to the development of clinical phenotypes and shape the progression of diseases. Our results can provide insight into developing personalized therapy to target a specific neurotoxic tau polymorph.
微管相关tau蛋白的聚集是几种神经退行性疾病的显著标志，如阿尔茨海默病（AD）、路易体痴呆（DLB）和进行性核上性麻痹（PSP）。tau寡聚体被认为是引发聚集并传播朊病毒样结构的主要神经毒性物质。此外，不同疾病的聚集tau具有不同的结构特征，称为多形体。在这里，我们研究了来自AD、DLB和PSP的扩增脑源性tau寡聚体（aBDTOs）的结构和功能差异。我们的结果表明，aBDTOs具有不同的结构和形态特征，这些特征会影响神经元功能、基因调控，并最终影响疾病进展。因此，不同的tau寡聚体多形体可能有助于临床表型的发展，并影响疾病的进展。我们的结果可为开发针对特定神经毒性tau多形体的个性化治疗提供见解。
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