Department of Molecular Pharmacology and Physiology, USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL 33613, USA.
Neurodegener Dis. 2013;11(4):165-81. doi: 10.1159/000337230. Epub 2012 Jul 10.
We aimed to investigate the influence of oligomeric forms of β-amyloid (Aβ) and the influence of the duration of exposure on the development of tau phosphorylation.
Aβ oligomers were injected intracranially either acutely into 5-month-old rTg4510 mice and tissue was collected 3 days later, or chronically into 3-month-old mice and tissue was collected 2 months later. Several forms of phosphorylated tau (p-tau), GSK3 (glycogen synthase kinase-3) and microglial and astrocyte activation were measured.
Acute injections of Aβ oligomers had no effect on p-tau epitopes but did result in elevation of phosphorylated/activated GSK3 (pGSK3). Chronic infusion of Aβ oligomers into the right hippocampus resulted in 3- to 4-fold elevations in several p-tau isoforms with no changes in total tau levels. A significant elevation in pGSK3 accompanied these changes. Microglial staining with CD68 paralleled the increase in tau phosphorylation, however, CD45 staining was unaffected by Aβ. Control experiments revealed that the infusion of Aβ from the minipumps was largely complete by 10 days after implantation. Thus, the elevation in p-tau 2 months after implantation implies that the changes are quite persistent.
Soluble Aβ(1-42) oligomers have long-lasting effects on tau phosphorylation in the rTg4510 model, possibly due to elevations in GSK3. These data suggest that even brief elevations in Aβ production, may have enduring impact on the risk for tauopathy.
我们旨在研究β-淀粉样蛋白（Aβ）寡聚体的影响，以及暴露时间对tau 磷酸化发展的影响。
将 Aβ 寡聚体急性或慢性注射到 rTg4510 小鼠的大脑中，急性注射组在 3 天后收集组织，慢性注射组在 2 个月后收集组织。测量几种磷酸化 tau（p-tau）、GSK3（糖原合酶激酶-3）以及小胶质细胞和星形胶质细胞的激活情况。
急性注射 Aβ 寡聚体对 p-tau 表位没有影响，但导致磷酸化/激活的 GSK3（pGSK3）升高。慢性将 Aβ 寡聚体注入右侧海马体导致几种 p-tau 同工型的 3 至 4 倍升高，而总 tau 水平没有变化。pGSK3 的显著升高伴随着这些变化。CD68 染色的小胶质细胞与 tau 磷酸化的增加平行，但 CD45 染色不受 Aβ 的影响。对照实验表明，植入后 10 天内，微型泵中的 Aβ 输注基本完成。因此，植入后 2 个月 p-tau 的升高意味着这些变化非常持久。
可溶性 Aβ（1-42）寡聚体在 rTg4510 模型中对 tau 磷酸化具有持久的影响，可能是由于 GSK3 的升高。这些数据表明，即使是短暂的 Aβ 产生升高，也可能对 tau 病的风险产生持久的影响。
