Core B - Biomarkers

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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.