The Development of a High Throughput Whole Brain Alzheimer's Disease Drug Screening Pipeline

Project Summary Alzheimer’s disease (AD) is a debilitating neurodegenerative disease affecting roughly 1 in 10 people over the age of 65. In 2017, the total cost of AD in the United States was estimated at $259 billion and is predicted to climb to $1.1 trillion by the year 2050. Despite enormous efforts invested in finding a cure, it has proven extremely difficult to develop treatments for AD. Contributing factors behind this difficulty is that AD is a complex, multifactorial disease, occurring over decades, and as CNS disease, is very difficult to study directly in the clinic. To address this challenge, the 2015 AD research summit set a goal to create and characterize a new generation of improved research models that would more faithfully reflect AD in humans. These new models hold enormous promise, but unfortunately contemporary tools are incomplete at best. Phenotypic whole brain methodologies, while providing a critical overview of the temporal and spatial progression of AD, have little corresponding molecular information. Meanwhile, in depth molecular methods remain confined to studying small portions of the brain due to time or cost limitations. This lack of an overview of the molecular mechanisms driving the spread of AD across the brain – a central aspect of AD in humans – leaves a crucial gap in our understanding of the etiology of the progression of AD and hinders the development of effective treatments. To bridge this gap, this proposal will build a flexible imaging and tissue processing platform to rapidly characterize AD rodent models that provides whole brain information while at the same time extends access to in-depth molecular information to facilitate crucial clinical translatability. This proposal combines teams from TissueVision and the NIA-funded MODEL-AD Center at The Jackson Laboratory who are experts in neuroscience, optical microscopy, imaging assays, and who have a successful commercialization history. Together, we will build on a set of impressive preliminary results mapping AD progression in whole brain datasets and produce a drug development pipeline to provide automated brain region mapping and combinatorial markers of AD pathology. We believe the synergy between instrumentation, biological assay development, and the next generation of AD research models represents an ideal partnership to develop next generation tools that hold the promise of finally developing effective treatments for AD.We propose to develop a novel whole brain imaging platform to rapidly screen Alzheimer’s Disease (AD) research models. The platform will identify regions of disease activity across the entire brain while at the same time allow researchers to interrogate the molecular mechanisms driving the spread of AD. It will provide researchers with a standardized framework allowing them to rapidly draw quantitative, detailed conclusions across therapeutic interventions and across rodent models, and ultimately make informed decisions on clinical translatability of potential therapeutics.