Tau and other proteins found in Alzheimer's disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans.
Tau and other proteins found in Alzheimer's disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans.
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DOI：
10.1126/scitranslmed.aba6334
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发表时间：
2020-11-25
影响因子：
17.1
通讯作者：
Small SA
中科院分区：
文献类型：
--
作者：
Simoes S;Neufeld JL;Triana-Baltzer G;Moughadam S;Chen EI;Kothiya M;Qureshi YH;Patel V;Honig LS;Kolb H;Small SA
内体运输已成为阿尔茨海默病（AD）的一个有缺陷的生物学途径，该途径是脑脊液（CSF）蛋白积累的来源。然而，在阿尔茨海默病内体运输途径缺陷设置中积累的CSF蛋白的身份仍然未知。在这里，我们对小鼠进行了脑脊液蛋白质组学筛选，神经元选择性敲除逆转录复合物VPS35的核心，VPS35是与AD有关的内体运输的主要导体。然后，我们验证了三个最相关的蛋白质组学发现：跨膜蛋白APLP1和CHL1的氨基端，以及已知在AD中非常规分泌和升高的tau的中间结构域。在AD痴呆患者中，脑脊液中氨基末端APLP1和CHL1的浓度与tau和磷酸化tau相关。在健康对照中观察到类似的结果，其中两种蛋白与tau和磷酸化tau相关，并且在约70%的AD前驱期患者中升高。总的来说，小鼠到人类的研究表明，逆转录物依赖的内体运输可以调节tau、APLP1和CHL1 CSF浓度，从而揭示了AD的运输途径如何促进疾病传播以及如何在体内识别其运输损伤。
Endosomal trafficking has emerged as a defective biological pathway in Alzheimer’s disease (AD), and the pathway is a source of cerebrospinal fluid (CSF) protein accumulation. Nevertheless, the identity of the CSF proteins that accumulate in the setting of defects in AD’s endosomal trafficking pathway remains unknown. Here, we performed a CSF proteomic screen in mice with a neuronal-selective knockout of the core of the retromer complex VPS35, a master conductor of endosomal traffic that has been implicated in AD. We then validated three of the most relevant proteomic findings: the amino terminus of the transmembrane proteins APLP1 and CHL1, and the mid-domain of tau, which is known to be unconventionally secreted and elevated in AD. In patients with AD dementia, the concentration of amino-terminal APLP1 and CHL1 in the CSF correlated with tau and phosphorylated tau. Similar results were observed in healthy controls, where both proteins correlated with tau and phosphorylated tau and were elevated in about 70% of patients in the prodromal stages of AD. Collectively, the mouse-to-human studies suggest that retromer-dependent endosomal trafficking can regulate tau, APLP1, and CHL1 CSF concentration, informing on how AD’s trafficking pathway might contribute to disease spread and how to identify its trafficking impairments in vivo.
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影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
了解细胞外TAU的复杂性有助于对阿尔茨海默氏病血液筛查的发展。
DOI：
10.1016/j.jalz.2018.09.010
发表时间：
2019-03
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Chen Z;Mengel D;Keshavan A;Rissman RA;Billinton A;Perkinton M;Percival-Alwyn J;Schultz A;Properzi M;Johnson K;Selkoe DJ;Sperling RA;Patel P;Zetterberg H;Galasko D;Schott JM;Walsh DM
通讯作者：
Walsh DM
影响因子：
12.7
作者：
Cicognola, Claudia;Brinkmalm, Gunnar;Hoglund, Kina
通讯作者：
Hoglund, Kina
影响因子：
4.8
作者：
Karch, Celeste M.;Jeng, Amanda T.;Goate, Alison M.
通讯作者：
Goate, Alison M.
影响因子：
4.2
作者：
Chu, Jin;Pratico, Domenico
通讯作者：
Pratico, Domenico