Establishment of a Human Microphysiological System to Elucidate Cellular Mechanisms Underlying Vulnerability to AD

Brigham And Women'S Hospital, Boston MA

Investigators

Abstract

Alzheimer’s disease (AD) manifests along a spectrum of neuropathological presentation, ages of onset and rates of cognitive decline. Genetic studies support a heterogeneous etiology, with over 70 associated loci, implicating several biological processes that mediate risk for AD. Vascular pathologies commonly occur in AD and have a strong influence on cognitive function. For example, moderate to severe cerebral amyloid angiopathy co-occurs in 47% of individuals with a diagnosis of Alzheimer’s dementia. In addition, several genes and pathways implicated in AD are expressed in cells of the blood-brain-barrier. Despite this, the majority of experimental systems for elucidating disease mechanisms and for testing new therapeutics are neither designed to capture the genetically complex drivers of AD nor do they recapitulate the complex intercellular interactions between peripheral blood mononuclear cells, endothelial cells, pericytes, astrocytes, microglia and neurons that occur at the neurovascular unit. Here, we will leverage a set of iPSC lines that we recently developed from over 100 participants in the Religious Order Study (ROS) and Memory and Aging Project (MAP) that span ethnically diverse populations and include deeply phenotyped and genome sequenced individuals to develop and optimize an improved all-human cellular system for studying AD and ADRDs. Over the past four years, we used an “Organ-on-Chip” 3D microfluidic device to develop an all-human iPSC-derived “Brain-Chip” that incorporates cells of the neurovascular unit including endothelial cells, pericytes, astrocytes, neurons, and microglia. Here, we have four overarching goals towards improving this system for the study of ADRDs: 1) To define the delivery conditions for the introduction of patient blood cells (PBMCs) and plasma into the Brain-Chip system, 2) To determine the physiological consequences of introduction of AD-relevant stressors on the integrity and molecular profiles of cells of the blood-brain barrier, 3) To establish an experimental model of cerebral amyloid angiopathy in the Brain-Chip system, and 4) To establish an experimental and analytic pipeline for quantifying responses to therapeutic interventions following delivery through the “blood” chamber in the Brain-Chip. Successful execution of this study will provide a platform for the scientific community which enables 1) the study of known and unknown genetic risk factors for dementia and 2) safety and efficacy testing of therapeutic interventions across diverse genetic backgrounds.