Modeling and Targeting Alzheimer’s Disease With Organoids

Abstract

Human neurodegenerative diseases, such as Alzheimer's disease (AD), are not easily modeled in vitro due to the inaccessibility of brain tissue and the level of complexity required by existing cell culture systems. Three-dimensional (3D) brain organoid systems generated from human pluripotent stem cells (hPSCs) have demonstrated considerable potential in recapitulating key features of AD pathophysiology, such as amyloid plaqueand neurofibrillary tangle-like structures. A number of AD brain organoid models have also been used as platforms to assess the efficacy of pharmacological agents in disease progression. However, despite the fact that stem cell-derived brain organoids mimic early aspects of brain development, they fail to model complex cell-cell interactions pertaining to different regions of the human brain and aspects of natural processes such as cell differentiation and aging. Here, we review current advances and limitations accompanying several hPSC-derived organoid methodologies, as well as recent attempts to utilize them as therapeutic platforms. We additionally discuss comparative benefits and disadvantages of the various hPSC-derived organoid generation protocols and differentiation strategies. Lastly, we provide a comparison of hPSC-derived organoids to primary tissue-derived organoids, examining the future potential and advantages of both systems in modeling neurodegenerative disorders, especially AD.

Enhanced Neuronal Activity and Asynchronous Calcium Transients Revealed in a 3D Organoid Model of Alzheimer’s Disease

“…Therefore, a detailed understanding of the pathophysiology underlying AD and the development of novel therapeutics are highly desirable. However, this remains quite challenging due to the experimental inaccessibility of the functional human brain 3 . Instead, in vitro model systems offer alternative and unprecedented opportunities to study AD, as they can recapitulate faithfully some key features involved in AD pathophysiology.…”

NEUBOrg: Artificially Induced Pluripotent Stem Cell-Derived Brain Organoid to Model and Study Genetics of Alzheimer’s Disease Progression

“…The horizontal layers of the cerebral cortex arranged from outer to inner include Layers 1–6 and the 4 main layers of the cerebellar cortex from outer to inner are also simulated. NEUBOrg platform, aiWBO simulations, was built based on the following comprehensive literature to provide genotypic and phenotypic markers for identifying cell types, brain regions and cortical layers ( Ahn et al, 2004 ; Logan et al, 2011 , 2020 ; Santos et al, 2011 ; Kirsch et al, 2012 ; Hattori, 2014 ; Lancaster and Knoblich, 2014 ; Lippmann et al, 2015 ; Zemke et al, 2015 ; Zhao et al, 2015 ; Tkachenko et al, 2016 ; Espuny-Camacho et al, 2018 ; Krefft et al, 2018 ; McKenzie et al, 2018 ; Qian et al, 2018 , 2019 ; Wang, 2018 ; Chen et al, 2019 , 2020 ; Do and Hong, 2019 ; Gerakis and Hetz, 2019 ; Kim et al, 2019 , 2020 ; Lancaster and Huch, 2019 ; Velasco et al, 2019 ; Bhaduri et al, 2020 ; Papaspyropoulos et al, 2020 ). A compilation of relevant markers is presented in Supplementary Tables S1–S5 .…”

Non-Canonical Functions of the ARF Tumor Suppressor in Development and Tumorigenesis

“…Mutations in key components of the Wnt cascade are responsible for the development of various types of cancer, such as melanomas, colorectal, and liver cancers [ 78 , 79 ]. Due to its major involvement in the regulation of stemness, Wnt pathway activation plays a critical role in patient-derived organoid formation, as it has been shown for several tissues such as colon, lung, and skin [ 80 , 81 , 82 , 83 ]. Inactivation of the Hippo pathway scaffold RASSF1A was found to be required for Wnt and Hippo pathway crosstalk resulting in maintenance of pluripotency, while RASSF1A uncouples Wnt from Hippo signaling to enable stem cell and embryonic differentiation towards all cell lineages, through p73 [ 65 ].…”