Department of Molecular Genetics
Center for Translational Neurodegeneration Research.
J Neurosci. 2021 Sep 1;41(35):7340-7349. doi: 10.1523/JNEUROSCI.0388-21.2021. Epub 2021 Jul 21.
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 (STEP). 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 STEP, prevents the dephosphorylation of GluA2, and concomitantly blocks mGluR-mediated LTD. By contrast, Reelin deficiency increased expression of Ca-permeable GluA2-lacking AMPA receptors along with higher STEP 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. 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β（Aβ）斑块和神经原纤维缠结的积累。Aβ寡聚体通过代谢型谷氨酸受体（mGluR）依赖性调节富含纹状体的酪氨酸磷酸酶（STEP），导致 AD 早期突触功能障碍，增强长时程抑郁（LTD；遗忘的范例）。 Reelin 是一种神经调节剂，通过 ApoE（载脂蛋白 E）受体发出信号，防止突触受到 Aβ毒性的影响（Durakoglugil 等人，2009）。 Reelin 信号受到 AD 最重要的遗传风险因素 ApoE4 的损害，而 Aβ-寡聚体激活代谢型谷氨酸受体（Renner 等人，2010）。因此，我们询问 Reelin 是否也会影响 mGluR-LTD。为此，我们使用 DHPG（二羟苯甘氨酸）诱导化学 mGluR-LTD，DHPG 是一种选择性 mGluR5 激动剂。我们发现外源性 Reelin 降低了 DHPG 诱导的 STEP 增加，防止了 GluA2 的去磷酸化，并同时阻断了 mGluR 介导的 LTD。相比之下，Reelin 缺乏会增加 Ca 可渗透的缺乏 GluA2 的 AMPA 受体的表达，同时 STEP 水平升高，导致海马 CA1 神经元中 DHPG 诱导的 LTD 被阻断。我们提出了一个模型，其中 Reelin 通过调节 mGluR 介导的信号转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退行性变具有重要意义。 Reelin 是一种重要的神经调节剂，在成年大脑中控制突触可塑性并防止神经退行性变。已经表明，淀粉样β通过内吞 NMDA 和 AMPA 受体利用 mGluR 诱导突触抑制，这种机制称为 LTD，是遗忘的范例。我们的结果表明，Reelin 调节磷酸酶 STEP，后者在神经退行性变中起重要作用，以及钙通透性 AMPA 受体的表达，其在记忆形成中起作用。这些数据表明，Reelin 使用 mGluR LTD 途径来调节记忆形成和神经退行性变。
