Dissecting Alzheimer's disease pathogenesis in human 2D and 3D models

Cenini, Giovanna; Hebisch, Matthias; Iefremova, Vira; Flitsch, Lea Jessica; Breitkreuz, Yannik; Tanzi, Rudolph E.; Kim, Doo Yeon; Peitz, Michael; Brüstle, Oliver

doi:10.1016/j.mcn.2020.103568

Cited by 35 publications

(32 citation statements)

References 158 publications

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“…Alternative models, such as 3D in vitro models (for example, organoids and 3D matrix cultures) could also have potential to provide mechanistic insights into AD-associated immune dysregulation 150 . Use of such 3D models is advancing rapidly, but further developments are needed if these experimental models are to improve our understanding of peripheral–central immune crosstalk.…”

Section: Roadmapmentioning

confidence: 99%

Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus

et al. 2021

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Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates that pathological alterations in central and peripheral immune responses that change over time. Considering AD as a systemic immune process raises important questions about how communication between the peripheral and central compartments occurs and whether this crosstalk represents a therapeutic target. We established a whitepaper workgroup to delineate the current status of the field and to outline a research prospectus for advancing our understanding of peripheral–central immune crosstalk in AD. To guide the prospectus, we begin with an overview of seminal clinical observations that suggest a role for peripheral immune dysregulation and peripheral–central immune communication in AD, followed by formative animal data that provide insights into possible mechanisms for these clinical findings. We then present a roadmap that defines important next steps needed to overcome conceptual and methodological challenges, opportunities for future interdisciplinary research, and suggestions for translating promising mechanistic studies into therapeutic interventions.

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Section: Roadmapmentioning

confidence: 99%

Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus

et al. 2021

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“…We next highlighted the cell lines that were most affected by knockout/knockdowns; given the challenge of functionally modeling AD in human systems 20 , these lines may provide alternatives that show aberrantly high expression of the selected AD-associated genes. For SPI1 in HL cell lines, these include NOMO1, THP1, MONOMAC1, THP1, and EOL1.…”

Section: Resultsmentioning

confidence: 99%

Genetic dependency of Alzheimer’s disease-associated genes across cells and tissue types

Jaladanki

Elmas

Malave

et al. 2021

Sci Rep

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Effective treatments targeting disease etiology are urgently needed for Alzheimer’s disease (AD). Although candidate AD genes have been identified and altering their levels may serve as therapeutic strategies, the consequence of such alterations remain largely unknown. Herein, we analyzed CRISPR knockout/RNAi knockdown screen data for over 700 cell lines and evaluated cellular dependencies of 104 AD-associated genes previously identified by genome-wide association studies (GWAS) and gene expression network studies. Multiple genes showed widespread cell dependencies across tissue lineages, suggesting their inhibition may yield off-target effects. Meanwhile, several genes including SPI1, MEF2C, GAB2, ABCC11, ATCG1 were identified as genes of interest since their genetic knockouts specifically affected high-expressing cells whose tissue lineages are relevant to cell types found in AD. Overall, analyses of genetic screen data identified AD-associated genes whose knockout or knockdown selectively affected cell lines of relevant tissue lineages, prioritizing targets for potential AD treatments.

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“…hPSCs, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), can propagate in vitro and differentiate into all adult cells, they therefore hold great promise for disease remodeling and drug discovery [ 2 – 5 ]. Particularly, the iPSCs derived from patients substantially facilitated us to recapitulate some of the disease-associated phenotypes with brain disorders from the cellular level [ 6 ]. Combination of genome-editing technology with hPSC model enables scientists to recapitulate any disease-associated mutations in cultured cells, and further correct of these genetic mutations in patient-derived iPSCs can be used to validate these phenotypes [ 7 – 9 ].…”

Section: Overview Of Hpdbosmentioning

confidence: 99%

Human pluripotent stem cell-derived brain organoids as in vitro models for studying neural disorders and cancer

Luo

2021

Cell Biosci

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The sheer complexities of brain and resource limitation of human brain tissue greatly hamper our understanding of the brain disorders and cancers. Recently developed three-dimensional (3D) brain organoids (BOs) are self-organized and spontaneously differentiated from human pluripotent stem cells (hPSCs) in vitro, which exhibit similar features with cell type diversity, structural organization, and functional connectivity as the developing human brain. Based on these characteristics, hPSC-derived BOs (hPDBOs) provide new opportunities to recapitulate the complicated processes during brain development, neurodegenerative disorders, and brain cancers in vitro. In this review, we will provide an overview of existing BO models and summarize the applications of this technology in modeling the neural disorders and cancers. Furthermore, we will discuss the challenges associated with their use as in vitro models for disease modeling and the potential future direction.

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Dissecting Alzheimer's disease pathogenesis in human 2D and 3D models

Cited by 35 publications

References 158 publications

Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus

Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus

Genetic dependency of Alzheimer’s disease-associated genes across cells and tissue types

Human pluripotent stem cell-derived brain organoids as in vitro models for studying neural disorders and cancer

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