Alzheimer’s Disease Patient Brain Extracts Induce Multiple Pathologies in Vascularized Neuroimmune Organoids for Disease Modeling and Drug Discovery
Posted on: 7 November 2024
Preprint posted on 28 October 2024
Categories: cell biology, immunology, neuroscience
Introduction
Alzheimer’s disease (AD) is a pervasive neurodegenerative condition that affects millions worldwide, yet effective treatments remain scarce. This gap in treatment options is largely due to the fact that common animal models used in clinical research often fail to replicate the complex processes of the human brain, creating a bottleneck for drug development targeted at prevention and finding a cure. Over the past decade, advancements in stem cell-derived brain organoids have allowed scientists to reconstruct the molecular mechanisms underlying neurodevelopmental and neurodegenerative diseases in vitro with remarkable accuracy. These miniature “brain avatars” grown in the lab have been used extensively to model the genetic and environmental factors driving AD progression. However until now, brain organoids were not reliable enough to efficiently and quickly recreate AD hallmarks.
In this study, the authors developed an innovative organoid platform that captures the cellular diversity of the human brain, including neurons, astrocytes, microglia, and vascular structures. These “Vascularized Neuroimmune Organoids” offer a unique way to simulate AD’s pathological progression in a dish, addressing limitations of previous protocols by reducing the time needed to observe AD markers.
Main results
Figure 1: General workflow of this study. hPSCs-derived neural progenitor cells (NPCs), primitive macrophage progenitors (PMPs), and vascular progenitors (VPs) are pooled together and grown under 3D conditions to generate vascularized neuroimmune organoids. Alzheimer’s Disease (AD) brain extract is then administered to organoids to drive AD phenotypes that are studied at the functional and molecular level.
Generation of Vascularized Neuroimmune Organoids
By combining neural, macrophage, and vascular progenitor cells, the authors successfully generated a brain organoid platform that includes the most relevant cell types responsible for cellular diversity in the human brain, from neurons and astrocytes to functional microglia and pseudo blood vessels.
Modeling AD progression in vitro
Yanru and colleagues then demonstrated that exposing these organoids to brain extracts derived from AD patients causes an increase in Amyloid-beta and Tau pathology in the surrounding mature neurons within just four weeks. These are typical hallmarks of AD that are difficult to reproduce in animal models. Additionally, they confirmed the involvement of microglia in disease progression and phenotypic manifestation by showing that these resident immune cells of the brain prune synaptic connectivity, phagocytose fibrillary deposits, and increase inflammation markers in the system—all consistent with known AD progression in the literature. Taken together, these findings highlight the capacity of Vascularized Neuroimmune Organoids to model key aspects of AD in a relatively straightforward, reliable, and potentially scalable way.
From bench to bedside
Interestingly, when treating organoids displaying AD-like phenotypes with Lecanemab, an FDA-approved monoclonal antibody for AD treatment, the authors demonstrated that the drug effectively reduced amyloid plaque levels by enhancing the microglia’s capacity to phagocytose these harmful deposits. This opens up new research avenues, as it suggests that brain organoid models like the one in this study could play a role in clinical research, helping to translate the therapeutic effects of drugs in a genetically and physiologically human-relevant context.
Conclusion/why I highlight this preprint
Overall, I really enjoyed going through this preprint as the experimental workflow and rationale behind each experiment are well documented and explained, successfully conveying the importance of the findings and their implications for the field. I love that the authors performed different experiments to corroborate their findings such as immunofluorescence, RT-PCR and electrical recordings. The results seem very solid and promising, moreover this platform not only represents a significant advancement for organoid-based disease modeling but also holds promise for applications in drug discovery and, potentially, clinical trial design.
Questions/future directions
- You highlight the complex cellular heterogeneity that your organoid model is able to capture, but this work lacks a detailed characterization of how different cell types and states are affected by the emergence of the AD phenotype in the organoids. Do you plan to perform single-cell analyses, such as scRNA-seq, to better characterize these effects? I believe this would provide additional insights into the results you presented.
- You show that your organoids contain vascular cells with functional morphology, yet the study didn’t address a vessel-mediated contribution to AD progression. Have you considered repeating the experiment using microglia-containing neural organoids that are not vascularized? It would be interesting to see if the vasculature might explain why the AD phenotype appears within just four weeks in your model.
- I think it would be fascinating to explore different genetic backgrounds in this context. For example, generating organoids with neural progenitors derived from patients with familial AD and microglia derived from healthy controls could help dissect how different genetic backgrounds drive varied responses to environmental triggers (like AD brain extracts) in specific cell populations. Have you considered experiments along these lines?
doi: https://doi.org/10.1242/prelights.38815
Read preprintSign up to customise the site to your preferences and to receive alerts
Register hereAlso in the cell biology category:
Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder
Harvey Roweth
Investigating Mechanically Activated Currents from Trigeminal Neurons of Non-Human Primates
Vanessa Ehlers
Motor Clustering Enhances Kinesin-driven Vesicle Transport
Sharvari Pitke
Also in the immunology category:
Alzheimer’s Disease Patient Brain Extracts Induce Multiple Pathologies in Vascularized Neuroimmune Organoids for Disease Modeling and Drug Discovery
Manuel Lessi
Global coordination of protrusive forces in migrating immune cells
yohalie kalukula
Integrin conformation-dependent neutrophil slowing obstructs the capillaries of the pre-metastatic lung in a model of breast cancer
Simon Cleary
Also in the neuroscience category:
Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder
Harvey Roweth
Investigating Mechanically Activated Currents from Trigeminal Neurons of Non-Human Primates
Vanessa Ehlers
Circadian modulation of mosquito host-seeking persistence by Pigment-Dispersing Factor impacts daily biting patterns
Javier Cavieres
preListscell biology category:
in theNovember in preprints – the CellBio edition
This is the first community-driven preList! A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. Categories include: 1) cancer cell biology 2) cell cycle and division 3) cell migration and cytoskeleton 4) cell organelles and organisation 5) cell signalling and mechanosensing 6) genetics/gene expression
List by | Felipe Del Valle Batalla et al. |
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
List by | Reinier Prosee |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
List by | Nadja Hümpfer et al. |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
List by | Alex Eve |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
List by | Ana Dorrego-Rivas |
BioMalPar XVI: Biology and Pathology of the Malaria Parasite
[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria
List by | Dey Lab, Samantha Seah |
1
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
List by | Paul Gerald L. Sanchez and Stefano Vianello |
ECFG15 – Fungal biology
Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome
List by | Hiral Shah |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
List by | Madhuja Samaddar et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
List by | Dey Lab |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
List by | Sandra Malmgren Hill |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
List by | Rob Hynds |
Cellular metabolism
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
List by | Pablo Ranea Robles |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
List by | Dey Lab |
MitoList
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
List by | Sandra Franco Iborra |
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
List by | Joseph Jose Thottacherry |
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
List by | Dey Lab, Amanda Haage |
Also in the immunology category:
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
List by | Helen Zenner |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
List by | Osvaldo Contreras |
Single Cell Biology 2020
A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.
List by | Alex Eve |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
List by | Sandra Malmgren Hill |
Antimicrobials: Discovery, clinical use, and development of resistance
Preprints that describe the discovery of new antimicrobials and any improvements made regarding their clinical use. Includes preprints that detail the factors affecting antimicrobial selection and the development of antimicrobial resistance.
List by | Zhang-He Goh |
Zebrafish immunology
A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.
List by | Shikha Nayar |
Also in the neuroscience category:
2024 Hypothalamus GRC
This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.
List by | Nathalie Krauth |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
List by | Alex Eve, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
List by | Helen Zenner |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
List by | Ana Dorrego-Rivas |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
List by | Madhuja Samaddar et al. |
SDB 78th Annual Meeting 2019
A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.
List by | Alex Eve |
Autophagy
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
List by | Sandra Malmgren Hill |
Young Embryologist Network Conference 2019
Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London
List by | Alex Eve |