Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer's disease pathogenesis.
Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer's disease pathogenesis.
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DOI：
10.1186/2051-5960-2-9
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发表时间：
2014-01-23
影响因子：
7.1
通讯作者：
Don AS
中科院分区：
文献类型：
--
作者：
Couttas TA;Kain N;Daniels B;Lim XY;Shepherd C;Kril J;Pickford R;Li H;Garner B;Don AS
晚发性阿尔茨海默病（AD）的最大遗传危险因素是载脂蛋白E（ApoE）的等位基因。ApoE调节强效神经保护信号脂质鞘氨醇1-磷酸（S1 P）的分泌。S1 P由鞘氨醇的磷酸化衍生，由鞘氨醇激酶1和2（SphK 1和2）催化，并且SphK 1正向调节海马神经元中的谷氨酸分泌和突触强度。近年来，随着免疫调节药物Fingolimod（一种S1 P模拟物）被批准用于复发性多发性硬化症，S1 P及其受体家族受到强烈的药理学关注。我们量化的S1 P水平在六个大脑区域，不同的影响AD病理，在一个队列的34个死后的大脑，分为四组的基础上Braak神经元缠结分期。S1 P随着Braak分期的增加而下降，这在受AD病理影响最严重的脑区中最为明显。与对照组相比，Braak III/IV期海马（p = 0.010）和下颞叶皮质（p = 0.014）中的S1 P/鞘氨醇比值分别低66%和64%。根据这种变化，SphK 1和SphK 2的活性随着海马中Braak病理学的增加而下降（分别为p = 0.032和0.047）。与ApoE 4携带者相比，ApoE 2携带者海马中S1 P/鞘氨醇比率高2.5倍，多变量回归显示APOE基因型与海马S1 P/鞘氨醇之间存在显著相关性（p = 0.0495），表明APOE基因型与AD易感性之间存在新的联系。这项研究表明，损失的S1 P和鞘氨醇激酶活性早期AD发病机制，并在AD诊断。我们的研究结果为进一步探索S1 P受体药理学在AD治疗中的作用奠定了基础。
The greatest genetic risk factor for late-onset Alzheimer's disease (AD) is the ϵ4 allele of Apolipoprotein E (ApoE). ApoE regulates secretion of the potent neuroprotective signaling lipid Sphingosine 1-phosphate (S1P). S1P is derived by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SphK1 and 2), and SphK1 positively regulates glutamate secretion and synaptic strength in hippocampal neurons. S1P and its receptor family have been subject to intense pharmacological interest in recent years, following approval of the immunomodulatory drug Fingolimod, an S1P mimetic, for relapsing multiple sclerosis. We quantified S1P levels in six brain regions that are differentially affected by AD pathology, in a cohort of 34 post-mortem brains, divided into four groups based on Braak neurofibrillary tangle staging. S1P declined with increasing Braak stage, and this was most pronounced in brain regions most heavily affected by AD pathology. The S1P/sphingosine ratio was 66% and 64% lower in Braak stage III/IV hippocampus (p = 0.010) and inferior temporal cortex (p = 0.014), respectively, compared to controls. In accordance with this change, both SphK1 and SphK2 activity declined with increasing Braak pathology in the hippocampus (p = 0.032 and 0.047, respectively). S1P/sphingosine ratio was 2.5-fold higher in hippocampus of ApoE2 carriers compared to ApoE4 carriers, and multivariate regression showed a significant association between APOE genotype and hippocampal S1P/sphingosine (p = 0.0495), suggesting a new link between APOE genotype and pre-disposition to AD. This study demonstrates loss of S1P and sphingosine kinase activity early in AD pathogenesis, and prior to AD diagnosis. Our findings establish a rationale for further exploring S1P receptor pharmacology in the context of AD therapy.
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DOI：
10.3233/jad-2011-111202
发表时间：
2012
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Filippov V;Song MA;Zhang K;Vinters HV;Tung S;Kirsch WM;Yang J;Duerksen-Hughes PJ
通讯作者：
Duerksen-Hughes PJ
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
3.1
作者：
Asle-Rousta, Masoumeh;Kolahdooz, Zeynab;Dargahi, Leila
通讯作者：
Dargahi, Leila
影响因子：
4.8
作者：
Brinkmann, V;Davis, MD;Lynch, KR
通讯作者：
Lynch, KR
影响因子：
4.2
作者：
He, Xingxuan;Huang, Yu;Schuchman, Edward H.
通讯作者：
Schuchman, Edward H.