Alzheimer's disease-replicated brain microphysiological system to model AD physiopathology and its influenceon gliovasculature and immune system

点击翻译按钮获取中文摘要

Abstract Two hallmarks of Alzheimers Disease are accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles, which disrupt brain function. Recent evidence indicates that dysfunction of cerebral vasculature and immune cell hyperactivity also play key roles in AD progression. There is no suitable in vitro model that reliably replicates the physiopathology or interaction of the neuro-gliovascular-immune system in humans. In addition, neither brain slice-based assays nor animal models replicate the full spectrum of human neuropathology and associated gliovascular-coupled inflammatory characteristics of AD. Early-onset familial AD (FAD) is a useful and representative model for studying various aspects of AD, since it is caused by a mutation in one of at least three knowns genes, presenilin 1, presenilin 2, and amyloid precursor protein (APP). We have developed a FAD-Brain MicroPhysiological System (FAD-BMPS) to model both healthy and FAD- relevant neuronal tissue with brain-derived extracellular matrix (ECM), and have tested the generation of essential pathological features and hallmarks of AD. In a pilot study, we established a neuro-gliovascular- immune unit of healthy BMPS by integrating neurons, astrocytes, microglia, and endothelial cells into two separate tissues: brain tissue and a membrane-free blood vessel. Our proof-of concept study also demonstrated the feasibility of AD hallmark generation and its impact on vascular and inflammatory responses. We propose to develop a 3D membrane-free microfluidic FAD-BMPS and to validate AD physiopathology by integrating 1) patient iPSC-derived FAD neuronal tissue with patient-derived ECM, 2) a microfluidic-based membrane-free gliovascular system, and 3) resident and circulating immune cells. We will use FAD-neurons and study AD hallmark generation, including phosphorylated tau deposit in neural cell and amyloid beta accumulation in the patient-derived extracellular matrix (ECM), as well as amyloid beta transport, absorption, and its mediated toxicity. We will compare gliovascular dysfunction and overactive inflammatory response in a FAD-BMPS with those from a healthy BMPS, assess AD pathology exacerbation, and test the efficacy of existing and investigational drugs in ameliorating FAD. This innovative project will combine the elegance of microfluidics-based high-throughput and high-content imaging capability with the complex interactions of brain tissue in AD. The most critical aspect of this study is employing a membrane-free neuro-gliovascular-immune system in a reproducible manner that can be generally applied to AD, providing realistic and clinically relevant data, and offering a platform for drug screening and personalized medicine. The PI Yeohung Yun, a bioengineer at NC A&T State University with considerable experience with brain microphysiological system development, is supported by a team of clinicians and stem cell scientists. If successful, this BMPS will serve as a platform for modeling AD, reducing animal use, filling the scientific gap between in vitro and in vivo models, and accelerating drug screening and discovery.