Identification and Quantitation of Novel ABI3 Isoforms Relative to Alzheimer's Disease Genetics and Neuropathology.
Identification and Quantitation of Novel ABI3 Isoforms Relative to Alzheimer's Disease Genetics and Neuropathology.
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阐明与阿尔茨海默病（AD）风险相关的遗传多态性的作用可能会为潜在机制提供新的见解。两种多态性暗示ABI 3是AD风险的调节剂。在这里，我们试图确定ABI 3亚型在人类AD和非AD大脑中表达，量化更丰富的亚型作为AD遗传学和神经病理学的功能，并提供这些新的亚型产生的蛋白质的初步体外表征。我们报告说，ABI 3的表达增加与AD的神经病理学，但不与AD的遗传学。APP/PS1小鼠的单细胞RNAseq显示Abi 3主要由小胶质细胞表达，包括疾病相关的小胶质细胞。在人脑中，鉴定了几种新的ABI 3同种型，包括外显子6部分或完全缺失的同种型。这些亚型的表达与总ABI 3表达密切相关，但不受AD遗传学的影响。最后，我们在转染细胞中对这些亚型进行了初步表征，发现虽然全长ABI 3在胞质溶胶中以分散的点状方式表达，但缺乏大部分或全部外显子6的亚型倾向于形成广泛的蛋白质聚集体。总之，ABI 3表达仅限于小胶质细胞，随着阿尔茨海默氏症神经病理学的增加而增加，并且包括当在体外表达时显示可变的聚集趋势的几种同种型。
Elucidating the actions of genetic polymorphisms associated with the risk of Alzheimer’s disease (AD) may provide novel insights into underlying mechanisms. Two polymorphisms have implicated ABI3 as a modulator of AD risk. Here, we sought to identify ABI3 isoforms expressed in human AD and non-AD brain, quantify the more abundant isoforms as a function of AD genetics and neuropathology, and provide an initial in vitro characterization of the proteins produced by these novel isoforms. We report that ABI3 expression is increased with AD neuropathology but not associated with AD genetics. Single-cell RNAseq of APP/PS1 mice showed that Abi3 is primarily expressed by microglia, including disease-associated microglia. In human brain, several novel ABI3 isoforms were identified, including isoforms with partial or complete loss of exon 6. Expression of these isoforms correlated tightly with total ABI3 expression but were not influenced by AD genetics. Lastly, we performed an initial characterization of these isoforms in transfected cells and found that, while full-length ABI3 was expressed in a dispersed punctate fashion within the cytosol, isoforms lacking most or all of exon six tended to form extensive protein aggregates. In summary, ABI3 expression is restricted to microglia, is increased with Alzheimer’s neuropathology, and includes several isoforms that display a variable tendency to aggregate when expressed in vitro.
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影响因子：
3.7
作者：
Bae, Jeomil;Sung, Bong Hwan;Song, Woo Keun
通讯作者：
Song, Woo Keun
影响因子：
9.3
作者：
Early, Alexandria N.;Gorman, Amy A.;Morganti, Josh M.
通讯作者：
Morganti, Josh M.
影响因子：
16.2
作者：
Bhaskar, Kiran;Konerth, Megan;Kokiko-Cochran, Olga N.;Cardona, Astrid;Ransohoff, Richard M.;Lamb, Bruce T.
通讯作者：
Lamb, Bruce T.
影响因子：
--
作者：
Davidson, Andrew J.;Ura, Seiji;Insall, Robert H.
通讯作者：
Insall, Robert H.
DOI：
10.1097/nen.0b013e31825018f7
发表时间：
2012-05
影响因子：
3.2
作者：
Nelson PT;Alafuzoff I;Bigio EH;Bouras C;Braak H;Cairns NJ;Castellani RJ;Crain BJ;Davies P;Del Tredici K;Duyckaerts C;Frosch MP;Haroutunian V;Hof PR;Hulette CM;Hyman BT;Iwatsubo T;Jellinger KA;Jicha GA;Kövari E;Kukull WA;Leverenz JB;Love S;Mackenzie IR;Mann DM;Masliah E;McKee AC;Montine TJ;Morris JC;Schneider JA;Sonnen JA;Thal DR;Trojanowski JQ;Troncoso JC;Wisniewski T;Woltjer RL;Beach TG
通讯作者：
Beach TG