Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles. Aβ oligomers cause synaptic dysfunction early in AD by enhancing long-term depression (LTD; a paradigm for forgetfulness) via metabotropic glutamate receptor (mGluR)-dependent regulation of striatal-enriched tyrosine phosphatase (STEP₆₁). Reelin is a neuromodulator that signals through ApoE (apolipoprotein E) receptors to protect the synapse against Aβ toxicity (Durakoglugil et al., 2009) Reelin signaling is impaired by ApoE4, the most important genetic risk factor for AD, and Aβ-oligomers activate metabotropic glutamate receptors (Renner et al., 2010). We therefore asked whether Reelin might also affect mGluR-LTD. To this end, we induced chemical mGluR-LTD using DHPG (Dihydroxyphenylglycine), a selective mGluR5 agonist. We found that exogenous Reelin reduces the DHPG-induced increase in STEP₆₁, prevents the dephosphorylation of GluA2, and concomitantly blocks mGluR-mediated LTD. By contrast, Reelin deficiency increased expression of Ca²⁺-permeable GluA2-lacking AMPA receptors along with higher STEP₆₁ levels, resulting in occlusion of DHPG-induced LTD in hippocampal CA1 neurons. We propose a model in which Reelin modulates local protein synthesis as well as AMPA receptor subunit composition through modulation of mGluR-mediated signaling with implications for memory consolidation or neurodegeneration.

SIGNIFICANCE STATEMENT Reelin is an important neuromodulator, which in the adult brain controls synaptic plasticity and protects against neurodegeneration. Amyloid-β has been shown to use mGluRs to induce synaptic depression through endocytosis of NMDA and AMPA receptors, a mechanism referred to as LTD, a paradigm of forgetfulness. Our results show that Reelin regulates the phosphatase STEP, which plays an important role in neurodegeneration, as well as the expression of calcium-permeable AMPA receptors, which play a role in memory formation. These data suggest that Reelin uses mGluR LTD pathways to regulate memory formation as well as neurodegeneration.

阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，其特征是淀粉样蛋白 β (Aβ) 斑块和神经原纤维缠结的积累。Aβ 寡聚体通过纹状体富集酪氨酸磷酸酶的代谢型谷氨酸受体 (mGluR) 依赖性调节增强长期抑郁症（LTD；健忘的范例），从而在 AD 早期引起突触功能障碍（步骤₆₁）。Reelin 是一种神经调节剂，通过 ApoE（载脂蛋白 E）受体发出信号以保护突触免受 Aβ 毒性。Durakoglugil 等人，2009 年) Reelin 信号受到 ApoE4 的损害，ApoE4 是 AD 最重要的遗传风险因素，Aβ-寡聚体激活代谢型谷氨酸受体 (雷纳等人，2010 年）。因此，我们询问 Reelin 是否也可能影响 mGluR-LTD。为此，我们使用选择性 mGluR5 激动剂 DHPG（二羟基苯基甘氨酸）诱导化学 mGluR-LTD。我们发现外源性 Reelin 减少了 DHPG 诱导的 STEP ₆₁增加，阻止了 GluA2 的去磷酸化，并同时阻断了 mGluR 介导的 LTD。相比之下，Reelin 缺乏增加了缺乏 Ca ^{2+ 可}渗透性 GluA2 的 AMPA 受体的表达以及更高的 STEP ₆₁水平，导致海马 CA1 神经元中 DHPG 诱导的 LTD 闭塞。我们提出了一个模型，其中 Reelin 通过调节 mGluR 介导的信号传导来调节局部蛋白质合成以及 AMPA 受体亚基组成，这对记忆巩固或神经变性有影响。

重要性声明Reelin 是一种重要的神经调节剂，它在成人大脑中控制突触可塑性并防止神经变性。淀粉样蛋白-β 已被证明使用 mGluR 通过 NMDA 和 AMPA 受体的内吞作用诱导突触抑制，这种机制称为 LTD，一种健忘的范例。我们的研究结果表明，Reelin 调节磷酸酶 STEP，它在神经变性中起重要作用，以及钙渗透性 AMPA 受体的表达，在记忆形成中发挥作用。这些数据表明 Reelin 使用 mGluR LTD 通路来调节记忆形成以及神经变性。