Department Biomedical and Biotechnological Sciences, University of Catania, Catania 95123, Italy.
Section of Neuroscience and Cell Biology, Department Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona 60020, Italy.
J Neurosci. 2019 Jul 24;39(30):5986-6000. doi: 10.1523/JNEUROSCI.0163-19.2019. Epub 2019 May 24.
Failure of anti-amyloid-β peptide (Aβ) therapies against Alzheimer's disease (AD), a neurodegenerative disorder characterized by high amounts of the peptide in the brain, raised the question of the physiological role of Aβ released at low concentrations in the healthy brain. To address this question, we studied the presynaptic and postsynaptic mechanisms underlying the neuromodulatory action of picomolar amounts of oligomeric Aβ (oAβ) on synaptic glutamatergic function in male and female mice. We found that 200 pm oAβ induces an increase of frequency of miniature EPSCs and a decrease of paired pulse facilitation, associated with an increase in docked vesicle number, indicating that it augments neurotransmitter release at presynaptic level. oAβ also produced postsynaptic changes as shown by an increased length of postsynaptic density, accompanied by an increased expression of plasticity-related proteins such as cAMP-responsive element binding protein phosphorylated at Ser133, calcium-calmodulin-dependent kinase II phosphorylated at Thr286, and brain-derived neurotrophic factor, suggesting a role for Aβ in synaptic tagging. These changes resulted in the conversion of early into late long-term potentiation through the nitric oxide/cGMP/protein kinase G intracellular cascade consistent with a cGMP-dependent switch from short- to long-term memory observed after intrahippocampal administration of picomolar amounts of oAβ These effects were present upon extracellular but not intracellular application of the peptide and involved α7 nicotinic acetylcholine receptors. These observations clarified the physiological role of oAβ in synaptic function and memory formation providing solid fundamentals for investigating the pathological effects of high Aβ levels in the AD brains. High levels of oligomeric amyloid-β (oAβ) induce synaptic dysfunction leading to memory impairment in Alzheimer's disease (AD). However, at picomolar concentrations, the peptide is needed to ensure long-term potentiation (LTP) and memory. Here, we show that extracellular 200 pm oAβ concentrations increase neurotransmitter release, number of docked vesicles, postsynaptic density length, and expression of plasticity-related proteins leading to the conversion of early LTP into late LTP and of short-term memory into long-term memory. These effects require α7 nicotinic acetylcholine receptors and are mediated through the nitric oxide/cGMP/protein kinase G pathway. The knowledge of Aβ function in the healthy brain might be useful to understand the causes leading to its increase and detrimental effect in AD.
抗淀粉样β肽（Aβ）治疗阿尔茨海默病（AD）的失败，AD 是一种以大脑中大量肽为特征的神经退行性疾病，这引发了一个问题，即在健康大脑中以低浓度释放的 Aβ的生理作用是什么。为了解决这个问题，我们研究了低皮摩尔浓度的寡聚体 Aβ（oAβ）对雄性和雌性小鼠突触谷氨酸能功能的神经调节作用的突触前和突触后机制。我们发现，200pm 的 oAβ 诱导频率增加和成对脉冲易化减少，与停靠囊泡数量增加相关，表明它在突触前水平增加神经递质释放。oAβ 还产生了突触后变化，表现为突触后密度长度增加，同时表达可塑性相关蛋白如磷酸化 Ser133 的 cAMP 反应元件结合蛋白、磷酸化 Thr286 的钙调蛋白依赖性激酶 II 和脑源性神经营养因子增加，表明 Aβ 在突触标记中的作用。这些变化通过一氧化氮/cGMP/蛋白激酶 G 细胞内级联反应导致早期长时程增强转化为晚期长时程增强，这与海马内给予皮摩尔浓度 oAβ 后观察到的从短期记忆到长期记忆的 cGMP 依赖性转换一致。这些效应仅在外源性而非细胞内应用肽时存在，并涉及α7 烟碱型乙酰胆碱受体。这些观察结果阐明了 oAβ 在突触功能和记忆形成中的生理作用，为研究 AD 大脑中高 Aβ 水平的病理作用提供了坚实的基础。高水平的寡聚体淀粉样β（oAβ）可导致阿尔茨海默病（AD）中的突触功能障碍和记忆损伤。然而，在皮摩尔浓度下，该肽是确保长时程增强（LTP）和记忆所必需的。在这里，我们表明，200pm 的 oAβ 浓度增加了神经递质的释放、停靠囊泡的数量、突触后密度长度以及可塑性相关蛋白的表达，导致早期 LTP 转化为晚期 LTP，短期记忆转化为长期记忆。这些效应需要α7 烟碱型乙酰胆碱受体，并通过一氧化氮/cGMP/蛋白激酶 G 途径介导。了解 Aβ 在健康大脑中的功能可能有助于理解导致其在 AD 中增加和产生有害作用的原因。
