Core B - Biomarkers

核心B -项目总结/摘要 生物标志物核心B将继续提供血脑屏障（BB B）方面的服务、资源和专业知识 以及项目1-3和所有项目的CSF和血浆中的神经血管单位（NVU）和AD（Aβ、tau、pTau）生物标志物 P01调查员。这包括AD高遗传风险个体（APOE 4携带者）和AD高遗传风险个体（APOE 4携带者）中的生物标志物。 AD风险较低的患者（APOE 3纯合子）（项目1和2），以及新型APOE敲入/敲入（KIF） 具有和不具有A β和tau病理学的小鼠系（项目3）。核心将提供基本的、量化的 与作为该计划一部分收集的成像和认知测量相关的分子测量。期间 在最初的P01预算期间，核心B已经开发并测试了一组新的37种BB B/NVU生物标志物 在>800个CSF人样品中用A β和tau生物标志物同时测量。数据已被使用 P01研究人员在几个高影响力的出版物中发表了项目1和项目2。CSF BBB/NVU和AD 生物标志物已经通过来自多个P01位点的位点特异性分析进行了验证。对于项目1和2，核心B 最近测试了人血浆中的一组生物标志物（例如，sPDGFR α，Δ β 40/Δ β 40，总tau，pTau-181）， 并且正在开发血浆中的另外的BBB/NVU生物标志物（例如，BBB紧密连接蛋白，S100 B，sTREM 2）。 对于项目3，核心B已开发并验证了小鼠CSF中所有拟定的30种BB B/NVU生物标志物 和血浆，使用转基因周细胞缺陷、APOE敲入、5xFAD和/或P301 S tau系。鼠标 BBB/NVU和AD生物标志物类似于各自的人类生物标志物，这允许我们直接 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） 数十年的BBB、NVU和脑血管系统研究经验和知识; 2）数年 与MSD（中尺度发现技术）科学家合作开发第一个可靠的 同时测量人和小鼠生物流体样品中的多种BBB/NVU生物标志物，包括 开发sPDGFR β、CypA、MMP 9、sLRP 1的新MSD检测方法; 3）建立并验证 与参与本P01的所有临床研究中心合作机构合作，包括USC ADRC（Chui，Schneider，Ringman， 乔，亚辛），帕萨迪纳（哈灵顿）亨廷顿医学研究所，华盛顿大学奈特 ADRC（Morris，Fagan，Benzinger），班纳阿尔茨海默病研究所（Reiman）/亚利桑那州马约诊所（Caselli），以及 与项目1- 3研究者一样-Zlokovic、Nation、Pa、Toga、Thompson、Jacobs、Coba博士的实验室， 霍尔茨曼和格里芬。对于人类（项目1，2）和小鼠（项目3）生物流体中的大多数BBB/NVU生物标志物， 核心B将使用MSD多重或单重平台;对于少数生物标志物，使用ELISA和Sima（见研究计划 图2）。在Zlokovic博士的领导下， USC，核心B将继续1）协调生物液体采集、处理和输送，2）分析CSF和血浆 BBB/NVU和AD生物标志物，并进行APOE基因分型，3）提供技术开发， 4)促进数据管理、请求和向项目分发，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.