Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers.
Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers.
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DOI：
10.1126/scitranslmed.3005615
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发表时间：
2013-06-12
影响因子：
17.1
通讯作者：
Bateman RJ
中科院分区：
文献类型：
--
作者：
Potter R;Patterson BW;Elbert DL;Ovod V;Kasten T;Sigurdson W;Mawuenyega K;Blazey T;Goate A;Chott R;Yarasheski KE;Holtzman DM;Morris JC;Benzinger TL;Bateman RJ
阿尔茨海默氏病被假设是由淀粉样β（Aβ）肽的过度产生或清除减少引起的。由早老素（PSEN）基因突变引起的常染色体显性阿尔茨海默病（ADAD）被认为是由于中枢神经系统（CNS）中Aβ42相对于Aβ40的产生增加所致。这已在ADAD啮齿动物模型中得到证实，但在人类突变携带者中未得到证实。我们在PSEN突变的人类携带者和相关非携带者中使用稳定同位素标记动力学（SILK）研究的房室模型，以评价PSEN1和PSEN2突变对Aβ亚型产生和周转的病理生理学影响。我们通过使用淀粉样蛋白示踪剂匹兹堡化合物B（PiB）的正电子发射断层扫描（PET）测量的突变状态和纤维状淀粉样蛋白沉积量来比较这些发现。突变携带者的CNS Aβ42至Aβ40生成率比非携带者高24%，这与PET PiB成像定量的纤维状淀粉样蛋白沉积无关。在突变携带者中，可溶性Aβ42相对于Aβ40的部分转换率快65%，并且与淀粉样蛋白沉积相关，这与Aβ42在斑块中沉积增加导致脑脊液（CSF）中Aβ42回收率降低一致。在存在斑块的情况下，观察到Aβ42肽与预先存在的未标记肽发生可逆交换。这些发现支持了以下假设：在患有导致AD的早老素突变的人的CNS中，Aβ42过量产生，并证明在存在淀粉样斑块的情况下，可溶性Aβ42的周转和交换过程发生改变，导致CSF中Aβ42浓度降低。
Alzheimer’s disease is hypothesized to be caused by an over-production or reduced clearance of amyloid-beta (Aβ) peptide. Autosomal Dominant Alzheimer’s Disease (ADAD) caused by mutations in the presenilin (PSEN) gene have been postulated to result from increased production of Aβ42 compared to Aβ40 in the central nervous system (CNS). This has been demonstrated in rodent models of ADAD but not in human mutation carriers We used compartmental modeling of stable isotope labeling kinetic (SILK) studies in human carriers of PSEN mutations and related non-carriers to evaluate the pathophysiological effects of PSEN1 and PSEN2 mutations on the production and turnover of Aβ isoforms. We compared these findings by mutation status and amount of fibrillar amyloid deposition as measured by positron emission tomography (PET) using the amyloid tracer, Pittsburgh compound B (PiB). CNS Aβ42 to Aβ40 production rates were 24% higher in mutation carriers compared to non-carriers and this was independent of fibrillar amyloid deposits quantified by PET PiB imaging. The fractional turnover rate of soluble Aβ42 relative to Aβ40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Aβ42 into plaques leading to reduced recovery of Aβ42 in cerebrospinal fluid (CSF). Reversible exchange of Aβ42 peptides with pre-existing unlabeled peptide was observed in the presence of plaques. These findings support the hypothesis that Aβ42 is overproduced in the CNS of humans with presenilin mutations that cause AD, and demonstrate that soluble Aβ42 turnover and exchange processes are altered in the presence of amyloid plaques, causing a reduction in Aβ42 concentrations in the CSF.
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影响因子：
3.7
作者：
Cruchaga C;Haller G;Chakraverty S;Mayo K;Vallania FL;Mitra RD;Faber K;Williamson J;Bird T;Diaz-Arrastia R;Foroud TM;Boeve BF;Graff-Radford NR;St Jean P;Lawson M;Ehm MG;Mayeux R;Goate AM;NIA-LOAD/NCRAD Family Study Consortium
通讯作者：
NIA-LOAD/NCRAD Family Study Consortium
影响因子：
2.9
作者：
Esler, WP;Stimson, ER;Maggio, JE
通讯作者：
Maggio, JE
影响因子：
82.9
作者：
Bateman, Randall J.;Munsell, Ling Y.;Holtzman, David M.
通讯作者：
Holtzman, David M.
影响因子：
17.1
作者：
Iliff JJ;Wang M;Liao Y;Plogg BA;Peng W;Gundersen GA;Benveniste H;Vates GE;Deane R;Goldman SA;Nagelhus EA;Nedergaard M
通讯作者：
Nedergaard M
DOI：
10.1073/pnas.95.11.6448
发表时间：
1998-05-26
影响因子：
11.1
作者：
Lambert, MP;Barlow, AK;Klein, WL
通讯作者：
Klein, WL