AbMole小讲堂丨Amylin amide在代谢疾病和AD的细胞和动物模型中的应用

AbMole小讲堂丨Amylinamide（胰岛淀粉样肽）的作用机理，及其在糖尿病和阿尔茨海默症研究中的应用Amylinamide（胰岛淀粉样肽）是一种肽类调节剂，Amylinamide（AbMole，M10210）具有多种生理功能，例如调节β细胞、α细胞和δ细胞的激素分泌，以及抑制胰高血糖素、生长抑素和β肾上腺素受体介导的胰岛素分泌等。Amylinamide作为能量稳态的核心调节因子，为研究代谢调控机制、胰岛素抵抗、二型糖尿病（T2DM）和神经退行病变等动物模型提供了重要工具。Amylinamide（胰岛淀粉样肽）的作用机理Amylinamide（DAPamide，AbMole，M10210）是由37个氨基酸残基组成的线性多肽，其C端以酰胺化形式存在，这一结构特征对维持其生物学活性至关重要，酰胺化修饰可增强多肽的结构稳定性，减少被羧肽酶降解的概率，同时提升其与受体的亲和力。Amylin的第20-29个氨基酸区域被认为是“淀粉样核心结构域”，该区域具有高度的疏水性，并且倾向于形成β折叠片结构。在生理条件下的缓冲液中，其可通过疏水相互作用和氢键相互结合，转变为富含β折叠的寡聚体，并最终组装成原纤维和成熟的淀粉样纤维ADDINEN.CITE<EndNote><Cite><Author>Pittner</Author><Year>1994</Year><RecNum>1196</RecNum><DisplayText><styleface="superscript">[1]</style></DisplayText><record><rec-number>1196</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1759979032">1196</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Pittner,RichardA</author><author>Albrandt,Keith</author><author>Beaumont,Kevin</author><author>Gaeta,LaurieSL</author><author>Koda,JoyE</author><author>Moore,CandaceX</author><author>Rittenhouse,Judith</author><author>Rink,TimothyJ%JJournalofcellularbiochemistry</author></authors></contributors><titles><title>Molecularphysiologyofamylin</title></titles><pages>19-28</pages><volume>55</volume><number>S1994A</number><dates><year>1994</year></dates><isbn>0730-2312</isbn><urls></urls></record></Cite></EndNote>[1]。在生物体内，Amylinamide的主要合成场所是胰岛β细胞。Amylinamide一般在葡萄糖、氨基酸等促分泌信号的刺激下，与胰岛素共表达于β细胞产生的分泌颗粒中，并与胰岛素以1:100-1:200的比例共同释放至血液循环。除胰岛β细胞外，在中枢神经系统（如下丘脑、脑干）的部分神经元中也检测到Amylinamide的表达，这些中枢来源的Amylinamide可能通过旁分泌或自分泌方式参与食欲调控与能量平衡的调节。Amylinamide在血液中主要以游离形式存在。Amylinamide的受体主要是Calcitoninreceptor（CTR）与RAMP家族成员（主要为RAMP1、RAMP2、RAMP3）组成的异源二聚体，其中RAMP亚型是取决于受体细胞的组织特异性。当Amylinamide与受体结合后，可引起受体构象改变，激活胞内的G蛋白信号通路，包括Gαs/cAMP-PKA、Gαq/PLC-IP3/Ca²⁺等通路。图SEQ图\*ARABIC1.不同种属的Amylinamide及其修饰ADDINEN.CITE<EndNote><Cite><Author>Bower</Author><Year>2016</Year><RecNum>1236</RecNum><DisplayText><styleface="superscript">[2]</style></DisplayText><record><rec-number>1236</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760946227">1236</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Bower,RebekahL</author><author>Hay,DebbieL%JBritishjournalofpharmacology</author></authors></contributors><titles><title>Amylinstructure–functionrelationshipsandreceptorpharmacology:implicationsforamylinmimeticdrugdevelopment</title></titles><pages>1883-1898</pages><volume>173</volume><number>12</number><dates><year>2016</year></dates><isbn>0007-1188</isbn><urls></urls></record></Cite></EndNote>[2]Amylinamide（CASNo.：122384-88-7）的科研应用Amylinamide（DAPamide）用于代谢相关疾病模型构建与机制探究Amylinamide的错误折叠与聚集体的形成是2型糖尿病（T2DM）、肥胖相关胰岛功能损伤的因素之一。Amylin(1-37)（AbMole，M10210）的科研应用聚焦于疾病模型构建与病理机制的解析ADDINEN.CITE<EndNote><Cite><Author>Parveen</Author><Year>2023</Year><RecNum>1216</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>1216</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760679395">1216</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Parveen,R.</author><author>Harihar,D.</author><author>Chatterji,B.P.</author></authors></contributors><auth-address>FacultyofMedicineandHealthSciences,TampereUniversity,Tampere,Finland. SchoolofEngineeringSciencesinChemistry,BiotechnologyandHealth,KTHRoyalInstituteofTechnology,Stockholm,Sweden. FacultyofScience,AssamDownTownUniversity,Guwahati,India.</auth-address><titles><title>Recenthistonedeacetylaseinhibitorsincancertherapy</title><secondary-title>Cancer</secondary-title><alt-title>Cancer</alt-title></titles><periodical><full-title>Cancer</full-title><abbr-1>Cancer</abbr-1></periodical><alt-periodical><full-title>Cancer</full-title><abbr-1>Cancer</abbr-1></alt-periodical><pages>3372-3380</pages><volume>129</volume><number>21</number><edition>2023/08/10</edition><keywords><keyword>HDACinhibitors</keyword><keyword>HDACidrugs</keyword><keyword>Ptcl</keyword><keyword>cancer</keyword><keyword>combinationaltherapy</keyword><keyword>patents</keyword></keywords><dates><year>2023</year><pub-dates><date>Nov1</date></pub-dates></dates><isbn>0008-543x</isbn><accession-num>37560925</accession-num><urls></urls><electronic-resource-num>10.1002/cncr.34974</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[3]。在体外实验中，将纯化的Amylinamide加入胰岛β细胞（如INS-1细胞、原代胰岛细胞）培养体系，使其形成淀粉样聚集体，可模拟T2DM中β细胞凋亡、胰岛素分泌减少的病理过程ADDINEN.CITE<EndNote><Cite><Author>Jung</Author><Year>2019</Year><RecNum>1220</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>1220</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760923586">1220</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Jung,EM</author><author>Yoo,YM</author><author>Jeung,EB%JJPhysiolPharmacol</author></authors></contributors><titles><title>MelatonininfluencestheexpressionandoligomerizationofamylininratINS-1Ecells</title></titles><pages>695-703</pages><volume>70</volume><dates><year>2019</year></dates><urls></urls></record></Cite></EndNote>[4]，用于筛选抑制Amylin聚集体形成或保护β细胞的潜在生物活性分子；在体内实验中，通过给小鼠注射Amylinamide聚集体或构建Amylin突变体（如人源Amylin转基因小鼠），可建立胰岛淀粉样变性模型，研究β细胞功能衰退的动态机制ADDINEN.CITE<EndNote><Cite><Author>Bower</Author><Year>2016</Year><RecNum>1222</RecNum><DisplayText><styleface="superscript">[2]</style></DisplayText><record><rec-number>1222</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760924215">1222</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Bower,RebekahL</author><author>Hay,DebbieL%JBritishjournalofpharmacology</author></authors></contributors><titles><title>Amylinstructure–functionrelationshipsandreceptorpharmacology:implicationsforamylinmimeticdrugdevelopment</title></titles><pages>1883-1898</pages><volume>173</volume><number>12</number><dates><year>2016</year></dates><isbn>0007-1188</isbn><urls></urls></record></Cite></EndNote>[2]。Amylinamide聚集体可通过激活炎症通路（如NF-κB、NLRP3炎症小体）促进胰岛局部炎症，进而加重胰岛素抵抗ADDINEN.CITE<EndNote><Cite><Author>Cai</Author><Year>2011</Year><RecNum>1223</RecNum><DisplayText><styleface="superscript">[5]</style></DisplayText><record><rec-number>1223</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760924276">1223</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Cai,Kun</author><author>Qi,Dongfei</author><author>Hou,Xinwei</author><author>Wang,Oumei</author><author>Chen,Juan</author><author>Deng,Bo</author><author>Qian,Lihua</author><author>Liu,Xiaolong</author><author>Le,Yingying%JPloSone</author></authors></contributors><titles><title>MCP-1upregulatesamylinexpressioninmurinepancreaticβcellsthroughERK/JNK-AP1andNF-κBrelatedsignalingpathwaysindependentofCCR2</title></titles><pages>e19559</pages><volume>6</volume><number>5</number><dates><year>2011</year></dates><isbn>1932-6203</isbn><urls></urls></record></Cite></EndNote>[5]。在实验中常用Amylinamide处理细胞，检测胰岛素信号通路关键分子（如IRS-1、Akt）的磷酸化水平，或在动物模型中联合检测Amylin聚集体的水平与胰岛素抵抗指标（如HOMA-IR）的变化，以探究Amylin异常聚集与胰岛素抵抗的关联机制ADDINEN.CITE<EndNote><Cite><Author>Bishoyi</Author><Year>2021</Year><RecNum>1217</RecNum><DisplayText><styleface="superscript">[6,7]</style></DisplayText><record><rec-number>1217</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760682601">1217</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Bishoyi,AjitKumar</author><author>Roham,PratikshaH</author><author>Rachineni,Kavitha</author><author>Save,Shreyada</author><author>Hazari,MAsrafuddoza</author><author>Sharma,Shilpy</author><author>Kumar,Ashutosh%JBiologicalchemistry</author></authors></contributors><titles><title>Humanisletamyloidpolypeptide(hIAPP)-acurseintypeIIdiabetesmellitus:insightsfromstructureandtoxicitystudies</title></titles><pages>133-153</pages><volume>402</volume><number>2</number><dates><year>2021</year></dates><isbn>1437-4315</isbn><urls></urls></record></Cite><Cite><Author>Durrer</Author><Year>2015</Year><RecNum>1218</RecNum><record><rec-number>1218</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760682889">1218</key></foreign-keys><ref-typename="Thesis">32</ref-type><contributors><authors><author>Durrer,Alexandra</author></authors></contributors><titles><title>Invivoefficacyofhuman-derivedanti-amylinantibodiesinatransgenicmousemodelofdiabetesmellitus</title></titles><dates><year>2015</year></dates><publisher>UniversityofZurich</publisher><urls></urls></record></Cite></EndNote>[6,7]。Amylinamide（胰岛淀粉样肽）用于神经退行性疾病的相关研究近年研究发现，Amylinamide（AbMole，M10210）可在阿尔茨海默病（AD）动物模型的大脑中沉积，且与tau蛋白磷酸化、AmyloidβProtein（β淀粉样蛋白1-40，AbMole，M10194）等形成存在交互作用，因此其科研应用拓展至神经退行性疾病领域。在AD细胞模型（如SH-SY5Y神经细胞、原代神经元）中ADDINEN.CITE<EndNote><Cite><Author>Caruso</Author><Year>2018</Year><RecNum>1224</RecNum><DisplayText><styleface="superscript">[8]</style></DisplayText><record><rec-number>1224</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760924691">1224</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Caruso,Giuseppe</author><author>Fresta,ClaudiaG</author><author>Lazzarino,Giacomo</author><author>Distefano,DonatellaA</author><author>Parlascino,Paolo</author><author>Lunte,SusanM</author><author>Lazzarino,Giuseppe</author><author>Caraci,Filippo%JInternationaljournalofmolecularsciences</author></authors></contributors><titles><title>Sub-toxichumanamylinfragmentconcentrationspromotethesurvivalandproliferationofsh-sy5ycellsviathereleaseofvegfandhspb5fromendothelialrbe4cells</title></titles><pages>3659</pages><volume>19</volume><number>11</number><dates><year>2018</year></dates><isbn>1422-0067</isbn><urls></urls></record></Cite></EndNote>[8]，加入Amylinamide聚集体可诱导神经元凋亡、促进tau蛋白过度磷酸化（如p-TauSer396），同时抑制胰岛素信号在脑内的传导ADDINEN.CITE<EndNote><Cite><Author>Maletínská</Author><Year>2019</Year><RecNum>1225</RecNum><DisplayText><styleface="superscript">[9]</style></DisplayText><record><rec-number>1225</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760924831">1225</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Maletínská,Lenka</author><author>Popelová,Andrea</author><author>Železná,Blanka</author><author>Bencze,Michal</author><author>Kuneš,Jaroslav%JJournalofEndocrinology</author></authors></contributors><titles><title>TheimpactofanorexigenicpeptidesinexperimentalmodelsofAlzheimer’sdiseasepathology</title></titles><pages>R47-R72</pages><volume>240</volume><number>2</number><dates><year>2019</year></dates><isbn>0022-0795</isbn><urls></urls></record></Cite></EndNote>[9]；在AD转基因小鼠（如APP/PS1小鼠）中，通过联合检测脑内Amylin聚集体的含量与认知功能（如Morris水迷宫实验）的变化，可探究代谢紊乱（如T2DM）通过Amylin加重AD的分子机制ADDINEN.CITE<EndNote><Cite><Author>Baram</Author><Year>2016</Year><RecNum>1219</RecNum><DisplayText><styleface="superscript">[10]</style></DisplayText><record><rec-number>1219</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1760683210">1219</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Baram,Michal</author><author>Atsmon-Raz,Yoav</author><author>Ma,Buyong</author><author>Nussinov,Ruth</author><author>Miller,Yifat%JPhysicalChemistryChemicalPhysics</author></authors></contributors><titles><title>Amylin–Aβoligomersatatomicresolutionusingmoleculardynamicssimulations:alinkbetweenType2diabetesandAlzheimer'sdisease</title></titles><pages>2330-2338</pages><volume>18</volume><number>4</number><dates><year>2016</year></dates><urls></urls></record></Cite></EndNote>[10]。参考文献及鸣谢ADDINEN.REFLIST[1]RichardAPittner,KeithAlbrandt,KevinBeaumont,etal.,Molecularphysiologyofamylin,55(S1994A)(1994)19-28.[2]RebekahLBower,DebbieL%JBritishjournalofpharmacologyHay,Amylinstructure–functionrelationshipsandreceptorpharmacology:implicationsforamylinmimeticdrugdevelopment,173(12)(2016)1883-1898.[3]R.Parveen,D.Harihar,B.P.Chatterji,Recenthistonedeacetylaseinhibitorsinc