Core B - Biomarkers

核心B--项目摘要/摘要 Biomarker Core B将继续提供血脑屏障(BBB)方面的服务、资源和专业知识 以及脑脊液和血浆中的神经血管单位和AD(Aβ，tau，ptau)生物标记物 P01调查员。这包括阿尔茨海默病高遗传风险个体(APOE4携带者)和 那些AD风险较低的人(APOE3纯合子)(项目1和2)，以及新的APOE敲打/FLOX(KIF) 有和没有A和tau病理的小鼠品系(项目3)。核心将提供必要的、量化的 分子测量与作为本计划一部分收集的成像和认知测量相关。在.期间 在最初的P01‘S预算期间，核心B已经开发和测试了一组由37个BBB/NVU生物标志物组成的新面板 用A-和tau生物标记物同时测量&gt；800人脑脊液样本。这些数据已经被使用 由P01调查人员在几份影响较大的出版物上发表的项目1和2。脑脊液BBB/NVU与AD 生物标志物已经通过多个P01站点的特定站点分析得到了验证。对于项目1和2，核心B 最近在人血浆中检测了一组生物标志物(例如，sPDGFR，A40/A40，Total tau，ptau-181)， 并正在开发血浆中更多的BBB/NVU生物标记物(例如，BBB紧密连接蛋白、S100B、sTREM2)。 对于项目3，核心B已经开发并验证了小鼠脑脊液中所有拟议的30个BBB/NVU生物标记物 和血浆，使用转基因周细胞缺陷、APOE敲入、5xFAD和/或P301S tau系。鼠标 BBB/NVU和AD生物标记物与各自的人类生物标记物相似，这使得我们能够直接 比较人类(项目1和2)和小鼠(项目3)的研究结果。核心B的现有优势包括：1) 对血脑屏障、NVU和脑血管系统有几十年的研究经验和知识；2)几年 与MSD(中尺度发现技术)科学家合作开发第一个可靠的 人和小鼠生物体液样品中多种BBB/NVU生物标志物的同时检测 建立新的sPDGFR、CypA、MMP9、sLRP1mSD分析方法；3)建立和验证 与所有临床站点共同参与此次P01，包括南加州大学ADRC(Chui，Schneider，Ringman， 帕萨迪纳(哈林顿)亨廷顿医学研究所，华盛顿大学奈特 ADRC(Morris、Fagan、Benzinger)、Banner阿尔茨海默氏症研究所(Reiman)/亚利桑那州梅奥诊所(Caselli) 与项目1-3调查人员一样-Zlokovic博士、Nation、PA、Toga、Thompson、Jacobs、Coba、 霍兹曼和格里芬。对于人(项目1，2)和小鼠(项目3)生物体液中的大多数BBB/NVU生物标志物， 核心B将使用MSD多路或单路平台；对于一些生物标记物，将使用ELISA和SIMA(见资源计划 图2)。在Zlokovic博士和Zilkha神经发生研究所现有资源的领导下， 南加州大学，核心B将继续1)协调生物液的收集、处理和输送，2)检测脑脊液和血浆 针对BBB/NVU和AD生物标记物并进行APOE基因分型，3)提供技术进展，以及 4)促进数据管理、请求和向项目分发数据，以支持P01的科学目标。

CORE B – PROJECT SUMMARY/ABSTRACT The Biomarker Core B will continue to provide services, resources and expertise in blood-brain barrier (BBB) and neurovascular unit (NVU) and AD (Aβ, tau, pTau) biomarkers in CSF and plasma for Projects 1-3 and all P01 investigators. This includes biomarkers in individuals at high genetic risk for AD (APOE4 carriers) and in those at the lower risk for AD (APOE3 homozygotes) (Projects 1 and 2), and in novel APOE knock-inflox/flox (KIF) mouse lines with and without A and tau pathology (Project 3). The core will provide the essential, quantified molecular measures relatable to the imaging and cognitive measures collected as part of this program. During the initial P01’s budget period, Core B has developed and tested a novel panel of 37 BBB/NVU biomarkers measured simultaneously with A and tau biomarkers in >800 CSF human samples. The data have been used by Projects 1 and 2 in several high impact publications by P01 Investigators. The CSF BBB/NVU and AD biomarkers have been validated by site-specific analysis from multiple P01 sites. For Projects 1 and 2, Core B has recently tested a group of biomarkers in human plasma (e.g., sPDGFR, A40/A40, total tau, pTau-181), and is developing additional BBB/NVU biomarkers in plasma (e.g., BBB tight junction proteins, S100B, sTREM2). For Project 3, Core B has developed and validated all proposed 30 BBB/NVU biomarkers in the mouse CSF and plasma, using transgenic pericyte-deficient, APOE knock-in, 5xFAD and/or P301S tau lines. The mouse BBB/NVU and AD biomarkers are analogous to the respective human biomarkers, which allows us to directly compare findings in humans (Projects 1 and 2) and mice (Project 3). Existing strengths of Core B include: 1) decades of experience and knowledge in studying the BBB, NVU, and cerebrovascular system; 2) several years of experience working with MSD (Mesoscale Discovery Technology) scientists to develop the first reliable simultaneous measurements of multiple BBB/NVU biomarkers in biofluid samples in humans and mice including development of new MSD assays for sPDGFR, CypA, MMP9, sLRP1; 3) established and validated collaboration with all clinical site co-Is participating in this P01 including USC ADRC (Chui, Schneider, Ringman, Joe, Yassine), Huntington Medical Research Institute Pasadena (Harrington), Washington University Knight ADRC (Morris, Fagan, Benzinger), Banner Alzheimer’s Institute (Reiman)/ Mayo Clinic Arizona (Caselli), as well as with Project 1- 3 Investigators – laboratories of Drs. Zlokovic, Nation, Pa, Toga, Thompson, Jacobs, Coba, Holtzman and Griffin. For most BBB/NVU biomarkers in human (Project 1, 2) and mouse (Project 3) biofluids, Core B will use MSD multiplex or singleplex platforms; and for a few biomarkers ELISA and Sima (see Res. Plan Fig. 2). Under the leadership of Dr. Zlokovic and the resources available at the Zilkha Neurogenetic Institute at USC, Core B will continue to 1) coordinate biofluid collection, processing, and delivery, 2) assay CSF and plasma for BBB/NVU and AD biomarkers and conduct APOE genotyping, 3) provide technological developments, and 4) facilitate data management, requests and distribution to projects to support the scientific goals of the P01.