Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice.
Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice.
复制标题
表征 APP/PS1 小鼠淀粉样斑块的外观和生长。
DOI：
10.1523/jneurosci.2637-09.2009
复制
发表时间：
2009-08-26
影响因子：
5.3
通讯作者：
Lee, Jin-Moo
中科院分区：
文献类型：
--
作者：
Yan, Ping;Bero, Adam W.;Cirrito, John R.;Xiao, Qingli;Hu, Xiaoyan;Wang, Yan;Gonzales, Ernesto;Holtzman, David M.;Lee, Jin-Moo
淀粉样斑块主要由淀粉样β (a β)肽的细胞外聚集体组成，是阿尔茨海默病（AD）的病理标志。然而，影响体内淀粉样斑块形成和生长动力学的因素在很大程度上是未知的。通过APP/PS1转基因小鼠的薄颅骨窗口，使用连续活体多光子显微镜，我们发现淀粉样斑块在达到成熟大小之前出现并生长了数周。在最初斑块形成后的早期，斑块的生长更为明显：与10个月大的小鼠相比，6个月大的小鼠斑块生长得更快。斑块的生长速度也与大小有关，因为较小的斑块相对于较大的斑块表现出更快的生长。间质Aβ浓度的改变与斑块生长的变化有关。使用多光子显微镜和体内微透析的平行研究显示，可溶性细胞外a β的药理学减少仅为20-25%，与斑块形成和生长的急剧减少有关。此外，这种Aβ合成的微小减少足以减少6个月大的小鼠的淀粉样斑块负荷，而不是10个月大的小鼠，这表明在疾病发病机制的早期治疗可能比后期治疗更有效。与薄颅窗相比，开颅窗下未观察到明显的斑块生长，显示了广泛的小胶质细胞和星形胶质细胞活化。总之，这些发现表明，体内单个淀粉样斑块的生长持续数周，并可能受到间质a β浓度和反应性胶质瘤的影响。
Amyloid plaques are primarily composed of extracellular aggregates of amyloid-beta (Aβ) peptide and are a pathological signature of Alzheimer's disease (AD). However, the factors that influence the dynamics of amyloid plaque formation and growth in vivo are largely unknown. Using serial intravital multiphoton microscopy through a thinned-skull cranial window in APP/PS1 transgenic mice, we have found that amyloid plaques appear and grow over a period of weeks before reaching a mature size. Growth was more prominent early after initial plaque formation: plaques grew faster in 6 month-old compared to 10 month-old mice. Plaque growth rate was also size-related, as smaller plaques exhibited more rapid growth relative to larger plaques. Alterations in interstitial Aβ concentrations were associated with changes in plaque growth. Parallel studies using multiphoton microscopy and in vivo microdialysis revealed that pharmacological reduction of soluble extracellular Aβ by as little as 20-25% was associated with a dramatic decrease in plaque formation and growth. Furthermore, this small reduction in Aβ synthesis was sufficient to reduce amyloid plaque load in 6 month-old but not 10 month-old mice, suggesting that treatment early in disease pathogenesis may be more effective than later treatment. In contrast to thinned-skull windows, no significant plaque growth was observed under open-skull windows, which demonstrated extensive microglial and astrocytic activation. Together, these findings indicate that individual amyloid plaque growth in vivo occurs over a period of weeks and may be influenced by interstitial Aβ concentration as well as reactive gliosis.