Bioenergetic and inflammatory systemic phenotypes in Alzheimer's disease APOE ε4-carriers.
Bioenergetic and inflammatory systemic phenotypes in Alzheimer's disease APOE ε4-carriers.
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DOI：
10.1111/acel.13356
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发表时间：
2021-05
期刊：
影响因子：
7.8
通讯作者：
Swerdlow RH
中科院分区：
文献类型：
--
作者：
Wilkins HM;Wang X;Menta BW;Koppel SJ;Bothwell R;Becker AM;Anderson H;Schwartz E;Pei D;Yellapu NK;Chalise P;Gouvion CM;Haeri M;Burns JM;Swerdlow RH
我们研究了APOE ε4基因型对阿尔茨海默病（AD）患者血小板和淋巴细胞代谢的影响。APOE ε4携带者平均血小板线粒体细胞色素氧化酶Vmax活性降低，淋巴细胞凋亡标志物Annexin V显著升高。APOE ε4淋巴细胞中介导线粒体自噬和能量感知的蛋白含量较高，这可能代表了死后AD大脑中观察到的代偿性变化和概括现象。脂质合成途径分析发现APOE ε4淋巴细胞中AceCSI、ATP CL和磷酸化ACC水平升高。在死后脑组织中也观察到淋巴细胞ACC的变化。淋巴细胞RNAseq显示APOE ε4载体鞘脂转运蛋白3 （SPNS3）和整合素亚单位α 1 （ITGA1）表达降低。RNAseq通路分析显示APOE ε4等位基因激活炎症通路并调节生物能量信号。这些发现支持APOE基因型与生物能途径之间的关系，表明APOE ε4携带者的血小板和淋巴细胞存在生物能应激状态。无论是药物使用还是脑局限性阿尔茨海默病的组织病理学都不能解释这些发现，这些发现定义了APOE ε4决定的分子和系统表型，这些表型决定了阿尔茨海默病的病因。APOE调节阿尔茨海默病风险我们发现APOE基因型导致系统性表型。APOE ε4携带者的淋巴细胞和血小板表现出生物能量应激、线粒体功能障碍、细胞凋亡和炎症增加。
We examined the impact of an APOE ε4 genotype on Alzheimer's disease (AD) subject platelet and lymphocyte metabolism. Mean platelet mitochondrial cytochrome oxidase Vmax activity was lower in APOE ε4 carriers and lymphocyte Annexin V, a marker of apoptosis, was significantly higher. Proteins that mediate mitophagy and energy sensing were higher in APOE ε4 lymphocytes which could represent compensatory changes and recapitulate phenomena observed in post‐mortem AD brains. Analysis of the lipid synthesis pathway found higher AceCSI, ATP CL, and phosphorylated ACC levels in APOE ε4 lymphocytes. Lymphocyte ACC changes were also observed in post‐mortem brain tissue. Lymphocyte RNAseq showed lower APOE ε4 carrier sphingolipid Transporter 3 (SPNS3) and integrin Subunit Alpha 1 (ITGA1) expression. RNAseq pathway analysis revealed APOE ε4 alleles activated inflammatory pathways and modulated bioenergetic signaling. These findings support a relationship between APOE genotype and bioenergetic pathways and indicate platelets and lymphocytes from APOE ε4 carriers exist in a state of bioenergetic stress. Neither medication use nor brain‐localized AD histopathology can account for these findings, which define an APOE ε4‐determined molecular and systemic phenotype that informs AD etiology. APOE modulates Alzheimer's Disease Risk. We found that APOE genotype leads to a systemic phenotype. Lymphocytes and platelets from APOE ε4 carriers show increased bioenergetic stress, mitochondrial dysfunction, apoptosis, and inflammation.
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DOI：
10.1038/nrneurol.2017.185
发表时间：
2018-03
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Arnold SE;Arvanitakis Z;Macauley-Rambach SL;Koenig AM;Wang HY;Ahima RS;Craft S;Gandy S;Buettner C;Stoeckel LE;Holtzman DM;Nathan DM
通讯作者：
Nathan DM
影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1016/j.jalz.2011.03.005
发表时间：
2011-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
McKhann GM;Knopman DS;Chertkow H;Hyman BT;Jack CR Jr;Kawas CH;Klunk WE;Koroshetz WJ;Manly JJ;Mayeux R;Mohs RC;Morris JC;Rossor MN;Scheltens P;Carrillo MC;Thies B;Weintraub S;Phelps CH
通讯作者：
Phelps CH
影响因子：
20.1
作者：
Chawla A
通讯作者：
Chawla A