Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
PLoS One. 2011;6(9):e25416. doi: 10.1371/journal.pone.0025416. Epub 2011 Sep 28.
Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression.
先前的研究表明，诱导自噬可以改善与可溶性淀粉样蛋白-β（Aβ）积累相关的早期认知障碍。然而，诱导自噬对斑块和缠结的影响仍有待确定。虽然可溶性 Aβ和 tau 代表阿尔茨海默病（AD）发病机制中的毒性物质，但有充分的证据表明斑块和缠结也对正常大脑功能有害。因此，在具有已建立的斑块和缠结的动物模型中评估诱导自噬的效果至关重要。在这里，我们表明雷帕霉素在整个生命过程中预防性地给予 2 个月大的 3xTg-AD 小鼠时，会诱导自噬并显著减少斑块、缠结和认知缺陷。相比之下，在 15 个月大的 3xTg-AD 小鼠中诱导自噬，这些小鼠已经有了斑块和缠结，对 AD 样病理学和认知缺陷没有影响。总之，我们表明，雷帕霉素通过诱导自噬可能代表 AD 的一种有效的治疗策略，当在疾病进展的早期给药时。
