Department of Pathology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
Ann Neurol. 2011 May;69(5):819-30. doi: 10.1002/ana.22313. Epub 2011 Apr 6.
The goal of this study was to investigate the role of endogenous amyloid-β peptide (Aβ) in healthy brain.
Long-term potentiation (LTP), a type of synaptic plasticity that is thought to be associated with learning and memory, was examined through extracellular field recordings from the CA1 region of hippocampal slices, whereas behavioral techniques were used to assess contextual fear memory and reference memory. Amyloid precursor protein (APP) expression was reduced through small interfering RNA (siRNA) technique.
We found that both antirodent Aβ antibody and siRNA against murine APP reduced LTP as well as contextual fear memory and reference memory. These effects were rescued by the addition of human Aβ₄₂, suggesting that endogenously produced Aβ is needed for normal LTP and memory. Furthermore, the effect of endogenous Aβ on plasticity and memory was likely due to regulation of transmitter release, activation of α7-containing nicotinic acetylcholine receptors, and Aβ₄₂ production.
Endogenous Aβ₄₂ is a critical player in synaptic plasticity and memory within the normal central nervous system. This needs to be taken into consideration when designing therapies aiming at reducing Aβ levels to treat Alzheimer disease.
本研究旨在探究内源性淀粉样β肽（Aβ）在健康大脑中的作用。
通过海马脑片 CA1 区的细胞外场记录来检测长时程增强（LTP），这是一种被认为与学习和记忆有关的突触可塑性；同时采用行为学技术来评估情景性恐惧记忆和参考记忆。采用小干扰 RNA（siRNA）技术降低淀粉样前体蛋白（APP）的表达。
我们发现，抗啮齿动物 Aβ 抗体和针对鼠源 APP 的 siRNA 均可降低 LTP 以及情景性恐惧记忆和参考记忆。加入人源 Aβ₄₂后可挽救这些效应，表明内源性产生的 Aβ 对于正常的 LTP 和记忆是必需的。此外，内源性 Aβ 对可塑性和记忆的影响可能是通过调节递质释放、激活含α7 的烟碱型乙酰胆碱受体和 Aβ₄₂ 的产生来实现的。
内源性 Aβ₄₂ 是正常中枢神经系统内突触可塑性和记忆的关键参与者。在设计旨在降低 Aβ 水平以治疗阿尔茨海默病的治疗方法时，需要考虑到这一点。
