02430nas a2200325   4500000000100000000000100001008004100002260000900043653002000052653002100072653003500093653001900128653003300147100001700180700001700197700001100214700001700225700001700242700002000259700001900279700002500298700002200323700001600345245008800361856006700449300001200516490000600528520155600534022001402090       2021                            d  c202110abrain organoids10adisease modeling10ainduced pluripotent stem cells10aserum exposure10asporadic Alzheimer's disease1 aXianwei Chen1 aGuoqiang Sun1 aE Tian1 aMingzi Zhang1 aHayk Davtyan1 aThomas G. Beach1 aEric M. Reiman1 aMathew Blurton-Jones1 aDavid M. Holtzman1 aYanhong Shi00aModeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure  uhttps://onlinelibrary.wiley.com/doi/abs/10.1002/advs.202101462  a21014620 v83 aAlzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. Huge efforts have been made to develop anti-AD drugs in the past decades. However, all drug development programs for disease-modifying therapies have failed. Possible reasons for the high failure rate include incomplete understanding of complex pathophysiology of AD, especially sporadic AD (sAD), and species difference between humans and animal models used in preclinical studies. In this study, sAD is modeled using human induced pluripotent stem cell (hiPSC)-derived 3D brain organoids. Because the blood–brain barrier (BBB) leakage is a well-known risk factor for AD, brain organoids are exposed to human serum to mimic the serum exposure consequence of BBB breakdown in AD patient brains. The serum-exposed brain organoids are able to recapitulate AD-like pathologies, including increased amyloid beta (Aβ) aggregates and phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, and impaired neural network. Serum exposure increases Aβ and p-Tau levels through inducing beta-secretase 1 (BACE) and glycogen synthase kinase-3 alpha / beta (GSK3α/β) levels, respectively. In addition, single-cell transcriptomic analysis of brain organoids reveals that serum exposure reduced synaptic function in both neurons and astrocytes and induced immune response in astrocytes. The human brain organoid-based sAD model established in this study can provide a powerful platform for both mechanistic study and therapeutic development in the future.  a2198-3844