A cell therapy approach to restore microglial Trem2 function in a mouse model of Alzheimer’s disease
Open accessAbstract
Alzheimer's disease (AD) remains one of the grand challenges facing human society. Much controversy exists around the complex and multifaceted pathogenesis of this prevalent disease. Given strong human genetic evidence, there is little doubt, however, that microglia play an important role in preventing degeneration of neurons. For example, loss of function of the microglial gene Trem2 renders microglia dysfunctional and causes an early-onset neurodegenerative syndrome, and Trem2 variants are among the strongest genetic risk factors for AD. Thus, restoring microglial function represents a rational therapeutic approach. Here, we show that systemic hematopoietic cell transplantation followed by enhancement of microglia replacement restores microglial function in a Trem2 mutant mouse model of AD.
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Restoring microglial phagocytosis is therapeutically important.
“Many studies have underscored the therapeutic importance of restoring microglial phagocytosis (54–56).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [54]
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Favero, F., Re, A., Dason, M. S., Gravina, T., Gagliardi, M., Mellai, M., Corazzari, M., & Corà, D. (2024) · Biology Direct · doi:10.1186/s13062-024-00541-7 · Cited by 5 · see citing works
“However, despite the usefulness of transgenic mice in preclinical AD research [35–38], no comprehensive survey of the entire gut microbiota in AD models using shotgun metagenomics has yet been conducted.”
BackgroundMicroglial phagoptosis in development, health, and disease
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Luteolin as a novel therapeutic for diabetic kidney disease: Targeting the ADAM10-TREM2 pathway
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A myeloid trisomy 21-associated gene variant is protective from Alzheimer’s disease
Jin, M., Ma, Z., Dang, R., Zhang, H., Kim, R., Xue, H., Pascual, J. R., Yu, H., Papetti, A. V., Liú, Y., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02117-8 · Cited by 9 · see citing works
Laloli, K. J., Rentsch, P., Stayte, S., & Vissel, B. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1682979 · Cited by 2 · see citing works
The Roles of Macrophage Lineage Cells ( MLC s) in Brain Aging
Qin, Q., Zhang, L., Guo, M., Lu, D., Liu, Y., Wang, Z., Hu, M., Wang, S., Kang, X., Yi, H., et al. (2026) · CNS Neuroscience & Therapeutics · doi:10.1002/cns.70873 · Cited by 1 · see citing works
“The therapeutic potential of microglial replacement extends beyond a single disease entity, from AD [135] to lysosomal storage disorders [136], and highlights a universal mechanism whereby replenishment of the microglial compartment resets a dysregulated cerebral immune milieu and mitigates…”
Gateways for myeloid cell entry into the central nervous system
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“32 Here, we demonstrated that conditional deletion of Bmp4 in OPCs disrupted the transition of microglia into DAM and exacerbated A β plaque accumulation.”
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“45,46 Besides, a previous MR analysis reported that individuals with clonal hematopoiesis of indeterminate potential, a premalignant expansion of mutated hematopoietic stem cells, had a negative causal association with AD, 47 which is consistent with our results.”
Cell therapy and the skin: Great potential but in need of optimization
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Elp1 is required for myeloid differentiation and brain repopulation
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“…mice with amyloid pathology, systemic hematopoietic-cell transplantation followed by enhanced repopulation of the microglial niche by donor-derived myeloid cells introduced TREM2-competent myeloid-derived cells into the brain and restored important aspects of microglial function [56].”
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“While gene therapy and stem cell therapy also offer promising new directions in research [15–17], developing new approaches is necessary.”
Mr BMT Achieves Systemic Macrophage Replacement With Preservation of Tissue Homeostasis
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“…BMT) is one of our microglia replacement strategies [ 7 ], and it has shown promise for modeling and potentially treating diseases including adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) [ 9 ], Alzheimer’s disease (AD) [ 7, 10 ], and Prosaposin deficiency [ 11 ].”
Anti-inflammatory CAR-microglia targeting Aβ for Alzheimer’s disease therapy
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“Recent animal studies have been promising, revealing that peripherally derived myeloid cells can produce therapeutic effects in multiple neurodegenerative disease models [47–50].”
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Exploring retinal microglia: development, degeneration, and iPSC-derived model systems
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“…of healthy microglia has been reported to rescue neurological phenotypes in certain lysosomal storage disease models (Douvaras et al. 2024) and replacing native microglia in Alzheimer’s disease model mice with exogenous microglia has attenuated neurodegenerative progression (Yoo et al. 2023).”
Targeting Microglial Receptors for Alzheimer’s Disease: Translational Barriers from Bench to Bedside
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Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis
Walsh, A. E., Davis, B. A., Samuels, J. D., Mills, W. A., Thanos, J. M., Johnson, A. M., Moore, K. A., Puchalski, M. A., Steacy, E. J., Wendell, B. W., et al. (2026) · Journal of Experimental Medicine · doi:10.1084/jem.20260104
“…comparison with the recent advancements made in defining roles for innate immune pattern recognition receptors (e.g., TREM2, CLEC7A) and cytokine signaling (e.g., IL-1, type I IFN) in AD (Keren-Shaul et al., 2017; Mangalmurti et al., 2025; McQuade et al., 2020; Wang et al., 2016; Yoo et al., 2023).”
- Authors
- Yoo, Y., Neumayer, G., Shibuya, Y., Mader, M. M.-D., & Wernig, M.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Wernig, Marius
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2023-08
- Volume
- 30
- Issue
- 8
- Pages
- 1043-1053.e6
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W4385555459
- Cited by
- 109
- References
- 0
- Citations by year
- 2026: 31 · 2025: 39 · 2024: 34 · 2023: 5
- FWCI
- 11.18
- Type
- journal article
- Language
- en
- Update notices
- erratum (2023-10-05)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 368 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Alzheimer's disease, microglia, TREM2, cell therapy, hematopoietic stem cell transplantation, microglial dysfunction, neurodegeneration, genetic risk factors
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Membrane Glycoproteins, Neurons, Receptors, Immunologic, Microglia, Mice
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