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首页> 美国卫生研究院文献>The Journal of Neuroscience >Memantine Rescues Transient Cognitive Impairment Caused by High-Molecular-Weight Aβ Oligomers But Not the Persistent Impairment Induced by Low-Molecular-Weight Oligomers
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Memantine Rescues Transient Cognitive Impairment Caused by High-Molecular-Weight Aβ Oligomers But Not the Persistent Impairment Induced by Low-Molecular-Weight Oligomers

机译：美金刚可以挽救高分子量Aβ低聚物引起的短暂认知障碍但不能挽救低分子量低聚物引起的持续性损伤

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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.
机译：可溶性淀粉样β-低聚物（AβOs）的脑积聚与阿尔茨海默病（AD）的突触衰竭和认知障碍有关。但是，不同大小的寡聚物是否以及如何引起突触功能障碍是一个有争议的问题。在这里，我们报告低分子量（LMW）和高分子量（HMW）Aβ低聚物差异影响突触和记忆。单个脑室内注射LMWAβOs（10 pmol）会在小鼠中引起快速和持续的认知障碍。另一方面，发现由HMWAβOs（10 pmol）诱导的记忆缺陷是可逆的。虽然注射LMW低聚物的小鼠的记忆障碍与海马突触素和GluN2B免疫反应性降低有关，但在注射HMW低聚物的小鼠的海马中未检测到突触病理。另一方面，HMW低聚物而非LMW低聚物诱导海马神经元的氧化应激。美金刚能够挽救HMW低聚物引起的神经元氧化应激和短暂记忆障碍，但不能阻止LMW低聚物引起的持续性认知功能障碍。结果表明，不同的Aβ低聚物装配体以协调的方式起作用，诱导不同的病理学并导致突触功能障碍。此外，结果提示了美金刚在预防AD记忆丧失方面功效有限的机制解释。

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