Project Grant R44AG084491

A HIGH THROUGHPUT MULTIPLEXED PIPELINE FOR MODELS OF ALZHEIMER?S DISEASE - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) AFFECTS ROUGHLY 10% OF PEOPLE OVER THE AGE OF 65 IN THE UNITED STATES AND EXTRACTS AN ENORMOUS PERSONAL AND FINANCIAL TOLL ON THE NATION. DESPITE DECADES OF INVESTMENT THERE EXISTS NO CURE NOR EFFECTIVE TREATMENT. CONTRIBUTING FACTORS BEHIND THE DIFFICULTY INCLUDE THE COMPLEX, MULTIFACTORIAL NATURE OF AD ETIOLOGY THAT IS REFRACTORY TO DIRECT CLINICAL OBSERVATION ESPECIALLY IN ITS EARLY STAGES. AS SUCH, RESEARCH MODELS ARE OF PARAMOUNT IMPORTANCE AS THEY HOLD GREAT POTENTIAL TO REVEAL KEY MECHANISTIC DETAILS DRIVING THE PROGRESSION OF AD IN THE CLINIC. THIS IS OF PARTICULAR RELEVANCE TODAY AS THERE IS A GROWING CONSENSUS THAT THE A-BETA HYPOTHESIS MUST GIVE WAY TO APPROACHES THAT REFLECT THE COMPLEX, MULTIFACTORIAL NATURE OF AD. FORTUNATELY, NEW METHODS SUCH AS SPATIAL BIOLOGY ARE WELL SUITED TO CAPTURE THE COMPLEXITY OF PROTEIN NETWORKS IMPLICATED IN AD IN WAYS THAT TRADITIONAL HISTOLOGICAL ANALYSIS CANNOT. UNFORTUNATELY, HOWEVER, BARRIERS TO APPLY SPATIAL BIOLOGY IN WHOLE TISSUES AND ORGANS ARE SUBSTANTIAL, INCLUDING HIGH COST OF INSTRUMENTATION, TECHNICALLY COMPLEX WORKFLOWS, AND SUBSTANTIAL DATA MANAGEMENT, ANALYSIS, AND VISUALIZATION CHALLENGES. THIS PROPOSAL WILL HELP ELIMINATE THESE BARRIERS BY OFFERING A CONVENIENT FEE-FOR-SERVICE PLATFORM WHERE BRAINS CAN BE SENT TO BE IMAGED AND ANALYZED. HIGH VALUE REGION-OF-INTEREST TISSUE SECTIONS CAN BE QUICKLY IDENTIFIED AND SELECTED FOR SECONDARY SPATIAL BIOLOGY ANALYSES. THE ANALYZED TISSUE SECTIONS AND 3D DATASETS CAN THEN BE MAPPED BACK TO THEIR CORRECT LOCATION IN IN VIVO IMAGING AND BRAIN ATLASES SUCH AS THE ALLEN CCF. IMPORTANTLY, THIS PROJECT WILL BE BUILT ON A HIGH-PERFORMANCE CLOUD PLATFORM THAT CAN HANDLE MULTI-TERABYTE MULTIPLEXED DATASETS AND SERVE THEM EFFICIENTLY SUCH THAT RESEARCHERS CAN EASILY COMPARE TREATMENT EFFECTS ON A PER BRAIN REGION BASIS ACROSS AGE, SEX, AND MOUSE MODEL. THIS PROPOSAL EXTENDS THE SUCCESS OF A PREVIOUS NIA PROPOSAL THAT COMBINED TEAMS FROM TISSUEVISION AND THE NIA-FUNDED MODEL-AD CENTER AT THE JACKSON LABORATORY. TO BUILD ON THIS IMPRESSIVE PARTNERSHIP WE WILL BE ADDING BRUKER, INC. A $2.4B MANUFACTURER OF SCIENTIFIC INSTRUMENTS THAT IS CURRENTLY ADVANCING CUTTING-EDGE SPATIAL BIOLOGY APPROACHES, NOTABLY MALDI-IHC, WHICH WILL BE CAPABLE OF PERFORMING A 60+ PLEX IMAGING OF TISSUE DATASETS. IN ADDITION, THE SEATTLE VETERAN'S ADMINISTRATION WILL BE ASSISTING OUR SPATIAL PROFILING EFFORTS WITH IMAGING MASS CYTOMETRY ON ITS FLUIDIGM HYPERION SYSTEM. WE BELIEVE THE SYNERGY BETWEEN NEXT-GENERATION AD RESEARCH MODELS, ADVANCED SPATIAL BIOLOGY INSTRUMENTATION AND DATA ANALYSIS REPRESENTS AN IDEAL ALLIANCE THAT HOLDS THE PROMISE TO DELIVER AN EXTREMELY VALUABLE SET OF NEW TOOLS TO THE AD RESEARCH COMMUNITY THAT MAY FINALLY OPEN THE WAY FOR EFFECTIVE AD TREATMENTS.