Temporal dynamics of microglial neuroprotection during chronic Aß ‐treatment in human iPSC‐derived 3D neurospheres
Bibliographic record
Abstract
BACKGROUND: Murine models of Alzheimer's Disease (AD) have resulted in numerous discoveries leading to a better understanding of AD pathogenesis but results poorly translated to novel treatment options. Over the past years, iPSC-derived human neuronal cultures have been developed to better model AD in vitro. One key hallmark of AD is the presence of insoluble Aß plaques in the brain. To model this microenvironment a 3D tissue culture is needed to successfully study the complex neuron-glia-Aß interaction. Here we present human iPSC-derived 3D neurospheres for modelling severe amyloidosis through chronic Aß application. METHOD: Neurospheres were formed from iPSC-derived neuronal progenitor cells and expanded, differentiated and maintained for 60 days. Microglia were added to readily populate the tissue for the last 10 days of culture. Oligomeric Aß42 (∼35 nM) was added to the media chronically for 3 or 5 weeks. Neuronal activity was measured using GCAmP6f live imaging. Aß induced oxidative stress was quantified by using roGFP. Single nuclei RNA sequencing (NucSeq) was performed to obtain transcriptional data. RESULT: Neurospheres, consisting of neurons and astrocytes, display robust synchronized neuronal activity. Aß treatment induces the formation of plaque-like aggregates in the tissue within days. We found dysregulated neuronal activity and oxidative stress after 2-3 weeks while severe neuronal loss can be observed after 4-5 weeks. Infiltrating microglia display high phagocytic activity towards Aß and successfully reduced extracellular Aß deposits, loss of neuronal activity and oxidative stress when added early during the Aß treatment. Microglia transferred late during Ab exposure ameliorated neuronal death but fail to recover neuronal function or reduce oxidative stress at this time point. NucSeq allows identifying the transcriptional profile of each cell type and will be used to study cell type specific changes after Aß exposure with or without microglia. CONCLUSION: We here present a human 3D cell culture model allowing the formation of neurospheres and a chronic Aß stimulation protocol to mimic amyloidosis as a novel human AD in vitro model. Transplanting microglia at different time points during culture allows to study the temporal dynamics of neuroprotective properties of microglia presenting a unique novel approach to reveal new potential therapeutic pathways.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".