Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, D-37075 Göttingen, Germany.
Int J Mol Sci. 2021 May 14;22(10):5191. doi: 10.3390/ijms22105191.
The relationship between the two most prominent neuropathological hallmarks of Alzheimer's Disease (AD), extracellular amyloid-β (Aβ) deposits and intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFT), remains at present not fully understood. A large body of evidence places Aβ upstream in the cascade of pathological events, triggering NFTs formation and the subsequent neuron loss. Extracellular Aβ deposits were indeed causative of an increased tau phosphorylation and accumulation in several transgenic models but the contribution of soluble Aβ peptides is still controversial. Among the different Aβ variants, the N-terminally truncated peptide Aβ is among the most abundant. To understand whether soluble Aβ peptides impact the onset or extent of tau pathology, we have crossed the homozygous Tg4-42 mouse model of AD, exclusively expressing Aβ peptides, with the PS19 (P301S) tau transgenic model. Behavioral assessment showed that the resulting double-transgenic line presented a partial worsening of motor performance and spatial memory deficits in the aged group. While an increased loss of distal CA1 pyramidal neurons was detected in young mice, no significant alterations in hippocampal tau phosphorylation were observed in immunohistochemical analyses.
阿尔茨海默病（AD）的两个最突出的神经病理学特征——细胞外淀粉样蛋白-β（Aβ）沉积和细胞内过度磷酸化的 tau 积聚形成神经原纤维缠结（NFT）之间的关系目前仍不完全清楚。大量证据表明 Aβ 在病理事件级联反应的上游，引发 NFT 的形成和随后的神经元丢失。细胞外 Aβ 沉积确实导致了几种转基因模型中 tau 磷酸化和积聚的增加，但可溶性 Aβ 肽的作用仍存在争议。在不同的 Aβ 变体中，N 端截断的肽 Aβ 是最丰富的一种。为了了解可溶性 Aβ 肽是否影响 tau 病理学的发生或程度，我们将 Aβ 肽特异性表达的纯合 Tg4-42 AD 转基因小鼠与 PS19（P301S）tau 转基因模型进行了杂交。行为评估表明，由此产生的双转基因系在老年组表现出运动性能的部分恶化和空间记忆缺陷。虽然在年轻小鼠中检测到远端 CA1 锥体神经元的丢失增加，但在免疫组织化学分析中未观察到海马 tau 磷酸化的显著改变。
