Topic: Inflammation, microglia and astrocytes
Large-scale genetic and preclinical studies strongly implicate myeloid cells, particularly brain-resident macrophages, in the pathogenesis of Alzheimer’s disease (AD). Efferocytic clearance of apoptotic cells and other cholesterol-rich cellular debris is a core macrophage function and represents an active area of AD research. However, human tissue-resident macrophages remain difficult to model in vitro as they acquire their transcriptional and functional identities in response to signals from their host tissue microenvironment. Many existing differentiation protocols mimic human brain macrophage developmental trajectories, but these protocols rely either on multi-step cytokine cocktails and lengthy differentiation or transduction of multiple transcription factors, both of which introduce variability and complicate genetic manipulation. To address these limitations, we developed a simplified protocol that generates high-purity (>90% CD45+CD11b+) human iPSC-derived macrophage-like cells (iMacs) from cryopreservable erythro-myeloid progenitor (EMP)-like intermediates in 19 days, including a final 7-day maturation step driven by macrophage colony-stimulating factor (M-CSF) alone. Transcriptomic profiling reveals that iMacs show enrichment for phagocytic and lysosomal programs, processes integral to efferocytosis. At both the transcriptional and protein level, iMacs have higher expression of scavenger receptors such as CD36 , CD163 and MRC1 , and of AD risk genes such as TREM2 and APOE . Functionally, iMacs show enhanced phagocytic uptake of diverse substrates relative to iPSC-derived microglia, including carboxylated latex beads, zymosan, amyloid-β 1-42, and amyloid-β 1-40, and exhibit expanded lysosomal mass. Robust TREM2 expression and signaling make iMacs a sensitive platform for interrogating TREM2 biology, with markedly higher phosphorylation of SYK and PLCγ2 in response to TREM2 engagement compared to iPSC-derived microglia. iMacs also tolerate lipid-mediated siRNA transfection with high survival and knockdown efficiency, enabling rapid genetic perturbation of AD risk genes. Together, these features make iMacs a practical, scalable, and genetically tractable human macrophage model for studying the regulation and cell biology of core macrophage functions that are known to play critical roles in AD, aging, and other disorders.
Key findings
- Robust TREM2 expression and signaling make iMacs a sensitive platform for interrogating TREM2 biology, with markedly higher phosphorylation of SYK and PLCγ2 in response to TREM2 engagement compared to iPSC-derived microglia. iMacs also tolerate lipid-mediated siRNA transfection with high survival and knockdown efficiency, enabling rapid genetic perturbation of AD risk genes.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “ipsc”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Lee, H., Peppler, G. B., Sewell, M., Münch, A., Podleśny-Drabiniok, A., Kim, J. J., et al. (2026). A rapid, genetically-tractable human iPSC-derived model for studying tissue-resident macrophage biology in Alzheimer’s and other diseases. bioRxiv. https://doi.org/10.64898/2026.10.08.757653
Vancouver
Lee H, Peppler GB, Sewell M, Münch A, Podleśny-Drabiniok A, Kim JJ, et al. A rapid, genetically-tractable human iPSC-derived model for studying tissue-resident macrophage biology in Alzheimer’s and other diseases. bioRxiv. 2026. doi:10.64898/2026.10.08.757653.
BibTeX
@article{lee2026-ce9e4ee2,
author = {Lee, H. and Peppler, G. B. and Sewell, M. and Münch, A. and Podleśny-Drabiniok, A. and Kim, J. J. and Orrick, J. and Marcora, E. and others},
title = {{A rapid, genetically-tractable human iPSC-derived model for studying tissue-resident macrophage biology in Alzheimer’s and other diseases}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.08.757653},
url = {https://doi.org/10.64898/2026.10.08.757653}
}