Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, China.
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.
Mol Neurobiol. 2019 Sep;56(9):6168-6183. doi: 10.1007/s12035-019-1507-4. Epub 2019 Feb 8.
Microtubule-associated protein tau in Alzheimer's disease (AD) brain is hyperphosphorylated, truncated, and aggregated into neurofibrillary tangles. Oligomeric and hyperphosphorylated tau (Oligo-tau) isolated from AD brain captures and templates normal tau into filaments both in vitro and in vivo; this prion-like activity is believed to be responsible for the progression of neurofibrillary pathology in AD. The 3xTg-AD mouse model develops both Aβ and tau pathologies and thus gains popularity in preclinical studies of AD. Despite the histopathological similarity of the 3xTg-AD model to AD, biochemical authenticity of tau alterations in this model remains elusive. To investigate the biochemical basis of tau pathology in 3xTg-AD brain, we here compared pathological alterations of tau in the aged 3xTg-AD brain to those in AD brain. We found that in contrast to substantial high molecular weight smear tau (HMW-tau) lacking the N-terminal portion and hyperphosphorylated at multiple sites in AD brain, tau in 3xTg-AD mouse brain showed no detectable HMW-tau or truncation but slightly increased phosphorylation when normalized with total tau. In addition, AT8 immunostaining exhibited filamentous tau inclusions in AD brain, but predominantly truffle-like morphology in aged 3xTg-AD mouse brain. Further, Oligo-tau isolated from 3xTg-AD mice showed minimal potency in capturing tau in vitro and seeding tau aggregation in cultured cells when compared to AD Oligo-tau. These findings suggest that the alterations of tau in 3xTg-AD mouse brain differ from those in AD brain. In 3xTg-AD mice, the lack of N-terminal truncation, scarce SDS/reducing reagent-resistant HMW-tau, and minimal hyperphosphorylation may collectively result in low potency in prion-like activity of the Oligo-tau.
阿尔茨海默病（AD）脑中的微管相关蛋白 tau 发生过度磷酸化、截断和聚集形成神经纤维缠结。从 AD 脑中分离得到的寡聚和过度磷酸化 tau（Oligo-tau）在体外和体内均可捕获并将正常 tau 模板化为纤维；这种类朊病毒活性被认为是导致 AD 中神经纤维病理学进展的原因。3xTg-AD 小鼠模型同时发展出 Aβ和 tau 病理学，因此在 AD 的临床前研究中得到了广泛应用。尽管 3xTg-AD 模型在组织病理学上与 AD 相似，但该模型中 tau 变化的生化真实性仍然难以捉摸。为了研究 3xTg-AD 脑中 tau 病理学的生化基础，我们比较了 3xTg-AD 老年脑与 AD 脑中 tau 的病理改变。我们发现，与 AD 脑中大量存在缺乏 N 端部分且多个位点过度磷酸化的高分子量 tau（HMW-tau）不同，3xTg-AD 小鼠脑内 tau 没有检测到 HMW-tau 或截断，但当与总 tau 归一化时，磷酸化略有增加。此外，在 AD 脑中，AT8 免疫染色显示出丝状 tau 包涵体，但在老年 3xTg-AD 小鼠脑中主要呈松露样形态。此外，与 AD Oligo-tau 相比，从 3xTg-AD 小鼠中分离得到的 Oligo-tau 在体外捕获 tau 的能力和在培养细胞中诱导 tau 聚集的能力较弱。这些发现表明 3xTg-AD 小鼠脑中 tau 的变化与 AD 脑中的变化不同。在 3xTg-AD 小鼠中，缺乏 N 端截断、稀少的 SDS/还原剂抗性 HMW-tau 和低磷酸化水平可能共同导致 Oligo-tau 的类朊病毒活性较低。
