TBI-ADRD Modeling with a Team Science Approach (TBI-ADRD Team Science)

Abstract Summary We hypothesize that we can increase systemically develop a progressive murine TBI-ADRD model with internal and external validity with a “Team-Science”-based two-phase ADRD-relevant phenotype enrichment strategy. This 'Team Science' framework allows us to leverage and integrate the complementary experience and expertise

our 5-site multidisciplinary animal model testing team. This collaborative design aims to improve model reproducibility by testing each model at two sites, and the use of standard operation procedure (SOP), common data elements, (CDE) for method/data collection harmonization. At each stage, we will evaluate all data collected,

and model advancement are based on a multi-domain 'ADRD assessment: (a) development of robust ADRD- relevant neurocognitive and neurobehavioral deficit phenotypes (primary), (b) development of ADRD-relevant proteinopathy-linked neuropathologic phenotypes (primary), (c) Positive ex vivo proteinopathy signature using

brain lysate thioflavin-T protein aggregation assay, (d) progressiveness of neurobehavioral / proteinopathy phenotypes, and (e) cross-site reproducibility of ADRD phenotypic features. Aim 1. Phase I: Examine and screen for mouse strain determinants and TBI injury types that might favor post TBI-ADRD formation and progression. We will conduct a systematic screen of diverse mouse strain determinants

affecting TBI-ADRD formation, including four strains (e.g., CD1, CAST/EiJ, PWK/PhJ, C57BL/6) and two distinct TBI models (controlled cortical impact/CCI, and repeated close head injury/rCHI). At interim and terminal 18 month endpoints, we will apply a carefully selected multi-domain 'ADRD assessment panel’ (mentioned above)

to evaluate the development and progression of post-TBI ADRD-like neuropathologies, neurobiochemical/biomarker signatures, and neurocognitive/memory deficit assessments. The highest-ranked TBI-ADRD paradigm will advance to Phase II. Aim 2. Phase II. Using the selected mouse strain/injury model candidate, introduce and evaluate two TBI-ADRD model enrichment factors. We will introduce secondary ADRD-

augmentation factors, including neuroinflammation and mouse/human-derived pathologic seeding materials for polyproteinopathy transmission, The final deliverable of this project is an optimized, validated, and molecularly characterized murine TBI-ADRD model that accurately recapitulates the key progressive neuropathology,

neurobiochemical signatures/biomarker expressions, and cognitive deficit phenotypic features of human TBI- ADRD. Aim 3. Implement TBI-ADRD model dissemination to facilitate its use by other TBI investigators. We will commit resources necessary to facilitate the dissemination of our findings and enable other researchers to

reproduce our TBI-ADRD model and key findings and improve on it, All our SOP and data will be uploaded to the PRECISE-TBI endorsed OCD-TBI preclinical TBI data-sharing consortium for open access.