Suppression of amyloid-β secretion from neurons by cis-9, trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid,Journal of Neurochemistry

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Suppression of amyloid-β secretion from neurons by cis-9, trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2021-08-11 , DOI: 10.1111/jnc.15490
Saori Hata _{1,

2} , Kuniyuki Kano _{3,

4} , Kazunori Kikuchi ₅ , Shoichi Kinoshita ₂ , Yuriko Sobu _{2,

6} , Haruka Saito ₂ , Takashi Saito _{7,

8} , Takaomi C Saido ₇ , Yoshitake Sano ₉ , Hidenori Taru ₂ , Junken Aoki _{3,

4} , Hiroto Komano _{6,

10} , Taisuke Tomita ₅ , Shunji Natori ₁₁ , Toshiharu Suzuki _{2,

6}

Affiliation

Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan.
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Department of Neuropathology and Neurosciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Advanced Prevention and Research Laboratory for Dementia, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science Institute, Wako, Japan.
Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Japan.
Division of Neuroscience, School of Pharmacy, Iwate Medical University, Yahaba-cho, Japan.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Two common conjugated linoleic acids (LAs), cis-9, trans-11 CLA (c9,t11 CLA) and trans-10, cis-12 CLA (t10,c12 CLA), exert various biological activities. However, the effect of CLA on the generation of neurotoxic amyloid-β (Aβ) protein remains unclear. We found that c9,t11 CLA significantly suppressed the generation of Aβ in mouse neurons. CLA treatment did not affect the level of β-site APP-cleaving enzyme 1 (BACE1), a component of active γ-secretase complex presenilin 1 amino-terminal fragment, or Aβ protein precursor (APP) in cultured neurons. BACE1 and γ-secretase activities were not directly affected by c9,t11 CLA. Localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, the predominant site of APP cleavage by BACE1. The level of CLA-containing phosphatidylcholine (CLA-PC) increased dramatically in neurons incubated with CLA. Incorporation of phospholipids containing c9,t11 CLA, but not t10,c12 CLA, into the membrane may affect the localization of some membrane-associated proteins in intracellular membrane compartments. Thus, in neurons treated with c9,t11 CLA, reduced colocalization of APP with BACE1 in late endosomes may decrease APP cleavage by BACE1 and subsequent Aβ generation. Our findings suggest that the accumulation of c9,t11 CLA-PC/LPC in neuronal membranes suppresses the production of neurotoxic Aβ in neurons.

中文翻译：

顺式 9、反式 11-十八碳二烯酸（共轭亚油酸的异构体）抑制神经元中淀粉样蛋白 β 的分泌

两种常见的共轭亚油酸 (LA)，cis-9, trans-11 CLA (c9,t11 CLA) 和 trans-10, cis-12 CLA (t10,c12 CLA)，发挥各种生物活性。然而，CLA 对神经毒性淀粉样蛋白-β (Aβ) 产生的影响仍不清楚。我们发现 c9,t11 CLA 显着抑制了小鼠神经元中 Aβ 的产生。CLA 处理不影响 β 位点 APP 裂解酶 1 (BACE1)、活性 γ-分泌酶复合物早老素 1 氨基末端片段的组分或 Aβ 蛋白前体 (APP) 在培养的神经元中的水平。BACE1 和 γ-分泌酶活性不受 c9,t11 CLA 的直接影响。在用 c9,t11 CLA 处理的神经元中，BACE1 和 APP 在早期内体中的定位增加；同时，两种蛋白质的定位在晚期内体中减少，后者是 BACE1 切割 APP 的主要位点。在与 CLA 孵育的神经元中，含有 CLA 的磷脂酰胆碱 (CLA-PC) 的水平显着增加。将含有 c9,t11 CLA 但不含 t10,c12 CLA 的磷脂掺入膜中可能会影响某些膜相关蛋白在细胞内膜隔室中的定位。因此，在用 c9,t11 CLA 处理的神经元中，晚期内体中 APP 与 BACE1 的共定位减少可能会减少 BACE1 对 APP 的切割和随后的 Aβ 生成。我们的研究结果表明，c9,t11 CLA-PC/LPC 在神经元膜中的积累抑制了神经元中神经毒性 Aβ 的产生。进入膜可能会影响某些膜相关蛋白在细胞内膜隔室中的定位。因此，在用 c9,t11 CLA 处理的神经元中，晚期内体中 APP 与 BACE1 的共定位减少可能会减少 BACE1 对 APP 的切割和随后的 Aβ 生成。我们的研究结果表明，c9,t11 CLA-PC/LPC 在神经元膜中的积累抑制了神经元中神经毒性 Aβ 的产生。进入膜可能会影响某些膜相关蛋白在细胞内膜隔室中的定位。因此，在用 c9,t11 CLA 处理的神经元中，晚期内体中 APP 与 BACE1 的共定位减少可能会减少 BACE1 对 APP 的切割和随后的 Aβ 生成。我们的研究结果表明，c9,t11 CLA-PC/LPC 在神经元膜中的积累抑制了神经元中神经毒性 Aβ 的产生。

更新日期：2021-08-11

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