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

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.