Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Henry and Allison McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Cell Rep. 2021 May 18;35(7):109134. doi: 10.1016/j.celrep.2021.109134.
Axonal generation of Alzheimer's disease (AD)-associated amyloid-β (Aβ) plays a key role in AD neuropathology, but the cellular mechanisms involved in its release have remained elusive. We previously reported that palmitoylated APP (palAPP) partitions to lipid rafts where it serves as a preferred substrate for β-secretase. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are cholesterol-rich lipid rafts that are upregulated in AD. Here, we show that downregulating MAM assembly by either RNA silencing or pharmacological modulation of the MAM-resident sigma1 receptor (S1R) leads to attenuated β-secretase cleavage of palAPP. Upregulation of MAMs promotes trafficking of palAPP to the cell surface, β-secretase cleavage, and Aβ generation. We develop a microfluidic device and use it to show that MAM levels alter Aβ generation specifically in neuronal processes and axons, but not in cell bodies. These data suggest therapeutic strategies for reducing axonal release of Aβ and attenuating β-amyloid pathology in AD.
阿尔茨海默病（AD）相关淀粉样蛋白-β（Aβ）的轴突生成在 AD 神经病理学中起着关键作用，但涉及 Aβ 释放的细胞机制仍不清楚。我们之前曾报道过，棕榈酰化 APP（palAPP）会分配到富含胆固醇的脂筏中，在那里它是β-分泌酶的首选底物。线粒体相关内质网（ER）膜（MAMs）是富含胆固醇的脂筏，在 AD 中上调。在这里，我们表明通过 RNA 沉默或 MAM 驻留的 sigma1 受体（S1R）的药理学调节下调 MAM 组装会导致 palAPP 的 β-分泌酶切割减弱。MAMs 的上调促进 palAPP 向细胞表面、β-分泌酶切割和 Aβ 生成的转运。我们开发了一种微流控装置，并使用它表明 MAM 水平会特异性改变神经元突起和轴突中的 Aβ 生成，而不会改变细胞体中的 Aβ 生成。这些数据表明了减少 Aβ 轴突释放和减轻 AD 中 β-淀粉样蛋白病理的治疗策略。
