Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314, USA.
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-Innovation Center of Neuroregeneration, 19 Qixiu Road, Nantong, 226001, Jiangsu, China.
Acta Neuropathol Commun. 2021 Feb 17;9(1):28. doi: 10.1186/s40478-021-01127-4.
Neurofibrillary tangles (NFTs) made of abnormally hyperphosphorylated tau are a hallmark of Alzheimer's disease (AD) and related tauopathies. Regional distribution of NFTs is associated with the progression of the disease and has been proposed to be a result of prion-like propagation of misfolded tau. Tau in AD brain is heterogenous and presents in various forms. In the present study, we prepared different tau fractions by sedimentation combined with sarkosyl solubility from AD brains and analyzed their biochemical and pathological properties. We found that tau in oligomeric fraction (O-tau), sarkosyl-insoluble fractions 1 and 2 (SI-tau and SI-tau) and monomeric heat-stable fraction (HS-tau) showed differences in truncation, hyperphosphorylation, and resistance to proteinase K. O-tau, SI-tau, and SI-tau, but not HS-tau, were hyperphosphorylated at multiple sites and contained SDS- and β-mercaptoethanol-resistant high molecular weight aggregates, which lacked the N-terminal portion of tau. O-tau and SI-tau displayed more truncation and less hyperphosphorylation than SI-tau. Resistance to proteinase K was increased from O-tau to SI-tau to SI-tau. O-tau and SI-tau, but not SI-tau or HS-tau, captured tau from cell lysates and seeded tau aggregation in cultured cells. Heat treatment could not kill the prion-like activity of O-tau to capture normal tau. Hippocampal injection of O-tau into 18-month-old FVB mice induced significant tau aggregation in both ipsilateral and contralateral hippocampi, but SI-tau only induced tau pathology in the ipsilateral hippocampus, and SI-tau and HS-tau failed to induce any detectable tau aggregation. These findings suggest that O-tau and SI-tau have prion-like activities and may serve as seeds to recruit tau and template tau to aggregate, resulting in the propagation of tau pathology. Heterogeneity of tau pathology within AD brain results in different fractions with different biological and prion-like properties, which may pose a major challenge in targeting tau for development of effective therapeutic treatments.
神经原纤维缠结（NFTs）由异常过度磷酸化的 tau 组成，是阿尔茨海默病（AD）和相关 tau 病的标志。NFT 的区域分布与疾病的进展有关，并被提出是错误折叠 tau 类病毒样传播的结果。AD 脑中的 tau 是异质的，呈现出多种形式。在本研究中，我们通过从 AD 脑中的沉淀和 Sarkosyl 可溶性分离，制备了不同的 tau 分数，并分析了它们的生化和病理特性。我们发现，寡聚体（O-tau）、Sarkosyl 不溶性分数 1 和 2（SI-tau 和 SI-tau）以及单体热稳定分数（HS-tau）中的 tau 在截断、过度磷酸化和对蛋白酶 K 的抗性方面存在差异。O-tau、SI-tau 和 SI-tau（但不是 HS-tau）在多个位点过度磷酸化，并含有 SDS 和 β-巯基乙醇抗性高分子量聚集体，这些聚集体缺乏 tau 的 N 端部分。O-tau 和 SI-tau 的截断程度高于 SI-tau，过度磷酸化程度低于 SI-tau。对蛋白酶 K 的抗性从 O-tau 到 SI-tau 再到 SI-tau 增加。O-tau 和 SI-tau（但不是 SI-tau 或 HS-tau）从细胞裂解物中捕获 tau，并在培养细胞中引发 tau 聚集。热处理不能杀死 O-tau 捕获正常 tau 的类病毒样活性。将 O-tau 注入 18 个月大的 FVB 小鼠的海马中，导致双侧海马中均发生明显的 tau 聚集，但 SI-tau 仅在同侧海马中引起 tau 病理学改变，而 SI-tau 和 HS-tau 均未引起任何可检测到的 tau 聚集。这些发现表明，O-tau 和 SI-tau 具有类病毒样活性，可能作为招募 tau 和模板 tau 聚集的种子，导致 tau 病理学的传播。AD 脑中 tau 病理学的异质性导致不同的分数具有不同的生物学和类病毒样特性，这可能对靶向 tau 以开发有效的治疗方法构成重大挑战。
