Our lab has recently shown that the Sigma-2 Receptor/Transmembrane Protein 97 (TMEM97) and Progesterone Receptor Membrane Component 1 (PGRMC1) form a complex with the Low Density Lipoprotein Receptor (LDLR), and this intact complex is required for efficient uptake of lipoproteins such as LDL and apolipoprotein E (apoE). These receptors are expressed in the nervous system where they have implications in neurodegenerative diseases such as Alzheimer’s disease (AD), where apoE is involved in neuronal uptake and accumulation of Aβ42, eventually cascading into neurodegeneration, synaptic dysfunction, and ultimately, dementia. We hypothesize that the intact Sigma-2 receptor complex—TMEM97, PGRMC1, and LDLR—is necessary for internalization of apoE and Aβ42 monomers (mAβ42) and oligomers (oAβ42), and the disruption of the receptor complex inhibits uptake. The results of this study suggest that the intact Sigma-2 receptor complex is a binding site for mAβ42 and oAβ42, in the presence or absence of apoE2, apoE3, and apoE4. The loss or pharmacological inhibition of one or both of these proteins results in the disruption of the complex leading to decreased uptake of mAβ42 and oAβ42 and apoE in primary neurons. The TMEM97, PGRMC1, and LDLR complex is a pathway for the cellular uptake of Aβ42 via apoE dependent and independent mechanisms. This study suggests that the complex may potentially be a novel pharmacological target to decrease neuronal Aβ42 internalization and accumulation, which may represent a new strategy for inhibiting the rate of neurotoxicity, neurodegeneration, and progression of AD.

我们的实验室最近表明，Sigma-2 受体/跨膜蛋白 97 (TMEM97) 和孕酮受体膜成分 1 (PGRMC1) 与低密度脂蛋白受体 (LDLR) 形成复合物，并且需要这种完整的复合物才能有效摄取脂蛋白，如低密度脂蛋白和载脂蛋白 E (apoE)。这些受体在神经系统中表达，它们对神经退行性疾病如阿尔茨海默病 (AD) 有影响，其中 apoE 参与神经元摄取和 Aβ42 的积累，最终级联成神经变性、突触功能障碍，并最终导致痴呆。我们假设完整的 Sigma-2 受体复合物——TMEM97、PGRMC1 和 LDLR——是 apoE 和 Aβ42 单体 (mAβ42) 和寡聚体 (oAβ42) 内化所必需的，并且受体复合物的破坏会抑制摄取。该研究的结果表明，在存在或不存在 apoE2、apoE3 和 apoE4 的情况下，完整的 Sigma-2 受体复合物是 mAβ42 和 oAβ42 的结合位点。这些蛋白质中的一种或两种的丧失或药理学抑制导致复合物的破坏，导致原代神经元中 mAβ42 和 oAβ42 和 apoE 的摄取减少。TMEM97、PGRMC1 和 LDLR 复合物是通过 apoE 依赖和独立机制细胞摄取 Aβ42 的途径。这项研究表明，该复合物可能是减少神经元 Aβ42 内化和积累的新药理学靶点，这可能代表一种抑制神经毒性、神经变性和 AD 进展的新策略。