Alzheimer’s Disease Patient Brain Extracts Induce Multiple Pathologies in Vascularized Neuroimmune Organoids for Disease Modeling and Drug Discovery

Yanru Ji, Xiaoling Chen, Meek Connor Joseph, Jenna Lillie McLean, Yang Yang, Chongli Yuan, Jean-Christophe Rochet, Fei Liu, Ranjie Xu

Posted on: 7 November 2024

Preprint posted on 28 October 2024

What if we could model Alzheimer's in a dish? Well now we can!

Selected by Manuel Lessi

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?

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Author's response

Ranjie Xu shared

Q1 Response: Thanks for your kind suggestion. In the current version of the preprint, we characterized the effects of the AD-like pathologies had on neurons and microglia by performing immunostaining, MEA among other techniques. Indeed, a more detailed analysis into this aspect could shed light on the possible mechanisms behind the transitions into pathological states. We plan to perform a proteomics study to identify altered proteins and signaling pathways between control and AD organoids, and to compare these results with previously reported changes in AD patients. We hope this data can further validate the potential of the proposed organoid model of being used in the process of disease modeling and drug development for AD.

Q2 Response: As discussed in the manuscript, we believe the strong seeding ability of the brain extracts, along with the comprehensive cell type composition and their interactions in the organoids, may contribute to the effective induction of AD pathologies. This might involve the roles of blood vessels. In the current study, we are investigating whether we can recapitulate pathologies related to vasculatures, such as cerebral amyloid angiopathy (CAA). I think it is a great idea to dissect the roles of vasculatures in AD by comparing our microglia-containing organoid under AD context with or without vasculatures in the future.

Q3 Response: This is a very intriguing question. Combining different cell lines from patients and healthy people and comparing their responses in front of AD brain extracts exposure could definitely help understand the influence of genetic background on the pathologies. In addition to familial AD, I think including sAD line and other genetic risk factors, such as ApoE4/4, will also be valuable regarding the specific question.

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