School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil.
J Neurosci. 2013 Jun 5;33(23):9626-34. doi: 10.1523/JNEUROSCI.0482-13.2013.
Brain accumulation of soluble amyloid-β oligomers (AβOs) has been implicated in synapse failure and cognitive impairment in Alzheimer's disease (AD). However, whether and how oligomers of different sizes induce synapse dysfunction is a matter of controversy. Here, we report that low-molecular-weight (LMW) and high-molecular-weight (HMW) Aβ oligomers differentially impact synapses and memory. A single intracerebroventricular injection of LMW AβOs (10 pmol) induced rapid and persistent cognitive impairment in mice. On the other hand, memory deficit induced by HMW AβOs (10 pmol) was found to be reversible. While memory impairment in LMW oligomer-injected mice was associated with decreased hippocampal synaptophysin and GluN2B immunoreactivities, synaptic pathology was not detected in the hippocampi of HMW oligomer-injected mice. On the other hand, HMW oligomers, but not LMW oligomers, induced oxidative stress in hippocampal neurons. Memantine rescued both neuronal oxidative stress and the transient memory impairment caused by HMW oligomers, but did not prevent the persistent cognitive deficit induced by LMW oligomers. Results establish that different Aβ oligomer assemblies act in an orchestrated manner, inducing different pathologies and leading to synapse dysfunction. Furthermore, results suggest a mechanistic explanation for the limited efficacy of memantine in preventing memory loss in AD.
脑内可溶性淀粉样β寡聚物（AβOs）的积累与阿尔茨海默病（AD）中的突触功能障碍和认知障碍有关。然而，不同大小的寡聚物是否以及如何诱导突触功能障碍仍存在争议。在这里，我们报告低分子量（LMW）和高分子量（HMW）Aβ寡聚物对突触和记忆有不同的影响。单次侧脑室注射 LMW AβOs（10 pmol）可迅速引起小鼠持续的认知障碍。另一方面，我们发现 HMW AβOs（10 pmol）引起的记忆缺陷是可逆的。虽然 LMW 寡聚物注射小鼠的记忆损伤与海马突触小体素和 GluN2B 免疫反应性降低有关，但在 HMW 寡聚物注射小鼠的海马中未检测到突触病变。另一方面，HMW 寡聚物而非 LMW 寡聚物诱导海马神经元的氧化应激。美金刚可同时挽救 HMW 寡聚物引起的神经元氧化应激和短暂的记忆损伤，但不能预防 LMW 寡聚物引起的持续认知缺陷。结果表明，不同的 Aβ寡聚物组装以协调的方式发挥作用，诱导不同的病理学并导致突触功能障碍。此外，结果为美金刚预防 AD 中记忆丧失的有限疗效提供了一种机制解释。
