School of Biomed Sciences, Ulster University, Coleraine, United Kingdom.
PLoS One. 2010 Mar 22;5(3):e9764. doi: 10.1371/journal.pone.0009764.
Alzheimer disease (AD) is a neurodegenerative disorder for which there is no cure. We have investigated synaptic plasticity in area CA1 in a novel AD mouse model (APPPS1-21) which expresses the Swedish mutation of APP and the L166P mutation of human PS-1. This model shows initial plaque formation at 2 months in the neocortex and 4 months in the hippocampus and displays beta-amyloid-associated pathologies and learning impairments.
METHODOLOGY/PRINCIPAL FINDINGS: We tested long-term potentiation (LTP) and short term potentiation (paired-pulse facilitation, PPF) of synaptic transmission in vivo in area CA1 of the hippocampus. There was no difference in LTP or PPF at 4-5 months of age in APPPS1-21 mice compared to littermate controls. At 6 months of age there was also no difference in LTP but APPPS1-21 mice showed slightly increased PPF (p<0.03). In 8 months old mice, LTP was greatly impaired in APPPS-21 animals (p<0.0001) while PPF was not changed. At 15 months of age, APPPS1-21 mice showed again impaired LTP compared to littermate controls (p<0.005), and PPF was also significantly reduced at 80 ms (p<0.005) and 160 ms (p<0.01) interstimulus interval. Immunohistological analysis showed only modest amyloid deposition in the hippocampus at 4 and 6 months with a robust increase up to 15 months of age.
Our results suggest that increased formation and aggregation of beta amyloid with aging is responsible for the impaired LTP with aging in this mouse model, while the transient increase of PPF at 6 months of age is caused by some other mechanism.
阿尔茨海默病（AD）是一种神经退行性疾病，目前尚无治愈方法。我们研究了一种新型 AD 小鼠模型（APPPS1-21）中海马 CA1 区的突触可塑性，该模型表达了 APP 的瑞典突变和人 PS-1 的 L166P 突变。该模型在 2 个月时在新皮质和 4 个月时在海马中出现初始斑块形成，并表现出β淀粉样相关病理和学习障碍。
方法/主要发现：我们在海马 CA1 区体内测试了突触传递的长时程增强（LTP）和短程增强（成对脉冲易化，PPF）。与同窝对照相比，APPPS1-21 小鼠在 4-5 个月龄时 LTP 或 PPF 没有差异。在 6 个月龄时，LTP 也没有差异，但 APPPS1-21 小鼠的 PPF 略有增加（p<0.03）。在 8 个月大的小鼠中，APPPS-21 动物的 LTP 严重受损（p<0.0001），而 PPF 没有变化。在 15 个月龄时，与同窝对照相比，APPPS1-21 小鼠的 LTP 再次受损（p<0.005），80ms（p<0.005）和 160ms（p<0.01）刺激间隔的 PPF 也显著降低。免疫组织化学分析显示，在 4 个月和 6 个月时海马内仅有适度的淀粉样沉积，在 15 个月时则显著增加。
我们的结果表明，β淀粉样蛋白的形成和聚集随着年龄的增长而增加，是导致该小鼠模型中随年龄增长 LTP 受损的原因，而 6 个月时 PPF 的短暂增加则是由其他机制引起的。
