Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease

Data from Colom-Cadena et al Published in Acta Neuropathologica in 2024. Abstract: Synapse loss correlates with cognitive decline in Alzheimer’s disease, and soluble oligomeric amyloid beta (Aβ) is implicated in synaptic dysfunction and loss. An important knowledge gap is the lack of understanding of how Aβ leads to synapse degeneration. In particular, there has been difficulty in determining whether there is a synaptic receptor that binds Aβ and mediates toxicity. While many candidates have been observed in model systems, their relevance to human AD brain remains unknown. This is in part due to methodological limitations preventing visualization of Aβ binding at individual synapses. To overcome this limitation, we combined two high resolution microscopy techniques: array tomography and Förster resonance energy transfer (FRET) to image over 1 million individual synaptic terminals in temporal cortex from AD (n=11) and control cases (n=9). Within presynapses and postsynaptic densities, oligomeric Aβ generates a FRET signal with transmembrane protein 97. Further, amyloid beta generates a FRET signal with cellular prion protein, and postsynaptic density 95 within postsynapses. Transmembrane protein 97 is also present in a higher proportion of postsynapses in Alzheimer’s brain compared to controls. We inhibited Aβ / transmembrane protein 97 interaction in a mouse model of amyloidopathy by treating with the allosteric modulator CT1812. CT1812 drug concentration correlated negatively with synaptic FRET signal between transmembrane protein 97 and Aβ. In human induced pluripotent stem cell derived neurons, transmembrane protein 97 is present in synapses and colocalizes with Aβ when neurons are challenged with human Alzheimer’s brain homogenate. Transcriptional changes are induced by Aβ including changes in genes involved in neurodegeneration and neuroinflammation. CT1812 treatment of these neurons caused changes in gene sets involved in synaptic function. These data support a role for transmembrane protein 97 in the synaptic binding of Aβ in human Alzheimer’s disease brain where it may mediate synaptotoxicity.

本数据集数据源自Colom-Cadena等人2024年发表于《Acta Neuropathologica》的研究。摘要：阿尔茨海默病（Alzheimer’s Disease, AD）中突触丢失与认知衰退密切相关，可溶性寡聚态β淀粉样蛋白（amyloid beta, Aβ）被认为参与突触功能障碍及突触丢失过程。当前学界存在重要认知空白：尚不明确β淀粉样蛋白如何介导突触退行性病变。具体而言，学界始终难以确定是否存在能够结合β淀粉样蛋白并介导其毒性作用的突触受体。尽管在模型系统中已发现诸多潜在候选受体，但它们与人类阿尔茨海默病脑组织的相关性仍未明确。这一困境在一定程度上源于现有方法学局限，无法实现单突触水平上β淀粉样蛋白结合事件的可视化观测。为突破这一局限，本研究联合使用两种高分辨率显微技术：阵列断层扫描（array tomography）与福斯特共振能量转移（Förster resonance energy transfer, FRET），对阿尔茨海默病（AD）患者（n=11）及正常对照个体（n=9）的颞叶皮层中超过100万个独立突触终末进行成像观测。在突触前膜与突触后致密区中，寡聚态β淀粉样蛋白可与跨膜蛋白97（transmembrane protein 97）产生福斯特共振能量转移信号。此外，β淀粉样蛋白可与细胞朊蛋白以及突触后致密蛋白95（postsynaptic density 95）在突触后结构中产生福斯特共振能量转移信号。与正常对照相比，阿尔茨海默病（AD）患者脑组织中，跨膜蛋白97在突触后结构中的占比更高。本研究通过使用变构调节剂CT1812，在淀粉样蛋白病小鼠模型中抑制了β淀粉样蛋白与跨膜蛋白97的结合相互作用。CT1812的药物浓度与跨膜蛋白97和β淀粉样蛋白之间的突触福斯特共振能量转移信号呈负相关。在人类诱导多能干细胞分化神经元中，跨膜蛋白97表达于突触结构中；当神经元暴露于人类阿尔茨海默病脑组织匀浆时，跨膜蛋白97可与β淀粉样蛋白共定位。β淀粉样蛋白可诱导转录组改变，包括参与神经退行性病变与神经炎症的相关基因表达变化。使用CT1812处理此类神经元后，参与突触功能的基因集表达发生改变。上述数据证实，跨膜蛋白97在人类阿尔茨海默病脑组织中参与β淀粉样蛋白的突触结合过程，并可能介导突触毒性作用。