Modeling Sporadic Alzheimer's Disease in Human Brain Organoids under Serum Exposure

Abstract

Alzheimer'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 (A ) aggregates and phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, and impaired neural network. Serum exposure increases A and p-Tau levels through inducing beta-secretase 1 (BACE) and glycogen synthase kinase-3 alpha / beta (GSK3 / ) 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.

Protective Signature of IFNγ-Stimulated Microglia Relies on miR-124-3p Regulation From the Secretome Released by Mutant APP Swedish Neuronal Cells

“…Although our coculture system with immortalized cell lines is more advanced than monoculture systems, a big gap still exists between each of them and iPSCs-derived models and/or primary human cells, as depicted in Supplementary Figure S3 . Hence, it is essential to validate the neuroprotective potential of regulating miR-124 expression levels in more advanced human personalized AD models, as the three-dimensional spheroids and organoids ( Pomeshchik et al, 2020 ; Chen et al, 2021 ), not forgetting the possibility of new animal models ( Baglietto-Vargas et al, 2021 ; Le Bras, 2021 ). Future studies should also characterize the entire EXO cargo and use miR-124 cellular probing (fluorescent in situ hybridization) to assess its subcellular localization.…”

Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

“…Even if microglial cells were not studied directly in these organoids, an inflammatory response was observed suggesting that this pathological feature could be modeled in such 3D models. Moreover, it was recently shown that exposure of brain models to serum mimics age associated BBB breakdown ( Chen et al, 2021 ), providing a platform to look for effective treatments for disorders with an age component like ALS and FTD.…”

Generation of human embryonic stem cell-derived lung organoids

“…To date, the technology to generate human embryonic stem cell (hESC)-derived lung cells have changed from traditional two-dimensional (2D) monolayer cell-based differentiation to three-dimensional (3D) organoid differentiation ( Chen et al., 2017 , 2018 ; Dye et al., 2015 ; Kim et al., 2021 ; Li et al., 2021 ). Organoid models possess structural organization similar to the native organ and cell types from multiple germ layers, making them a physiologically complex model to investigate organ developmental processes, drug screening, regeneration and disease modeling in vitro ( Chen et al., 2020 , 2021 ; Clevers, 2016 ; Kim et al., 2021 ; Wang et al., 2021 ). However, current protocols use more cytokines/small molecules and require longer time to generate hESC-derived lung organoids (HLOs) ( Chen et al., 2017 ; Dye et al., 2015 , 2016 ; Strikoudis et al., 2019 ; Wang et al., 2020 ).…”