Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer’s disease
Open accessAbstract
Microglia are critical in brain development and Alzheimer's disease (AD) etiology. Down syndrome (DS) is the most common genetic developmental disorder and risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglial functions during DS brain development and in AD in DS. Using induced pluripotent stem cell (iPSC)-based organoid and chimeric mouse models, we report that DS microglia exhibit an enhanced synaptic pruning function, which alters neuronal synaptic functions. In response to human brain tissue-derived pathological tau, DS microglia undergo cellular senescence and exhibit elevated type-I-interferon signaling. Mechanistically, knockdown of Hsa21-encoded type I interferon receptors, IFNARs, rescues the DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide in vivo evidence that human microglia respond to pathological tau by exhibiting dystrophic phenotypes. Targeting IFNARs may improve DS microglial functions and prevent senescence.
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Increased inflammatory activity in the developing brain may drive microglia to excessively prune synapses and disrupt network refinement.
“However, genetic knockdown of type I IFN receptors reduces these phenotypes148, suggesting that increased inflammatory activity in the developing brain may drive microglia to excessively prune synapses and disrupt network refinement in the developing brain.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [148]
The Results section (‘Inhibiting the expression of IFNARs rescues the defective DS microglia development’; page unavailable) reports that elevated pruning by Down syndrome microglia impaired neurotransmission and synaptic plasticity, and that reducing IFNAR expression partially rescued these defects. This supports the proposed link between increased type I interferon signaling and excessive pruning in the developing-brain model. The paper does not directly assess network refinement or establish the same effect for inflammatory activity generally. (LLM, conf=0.82)
Experimental — accuracy not yet measuredRecent studies demonstrate that type I IFN signaling is essential for cognitive impairment in AD, impacting the neuroinflammatory network and contributing to neuropathogenic processes.
“recent studies that demonstrate how type I IFN signaling is essential for cognitive impairment in AD,78 not only impacting the neuroinflammatory network of the disease but also contributing to neuropathogenic processes.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [79]
The Discussion (page unavailable) links elevated type I IFN signaling to microglial activation, synaptic loss and senescence in AD-related models. The paper's own experiments concern Down syndrome microglia and pathological tau; they do not demonstrate that IFN signaling is essential for cognitive impairment in AD. Its suggestion that targeting IFNARs might slow AD progression is more tentative than the citing sentence. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia derived from T21 iPSCs exhibit increased IFN signalling and over-prune synapses in vitro.
“Specifically, microglia derived from T21 iPSCs exhibit increased IFN signalling and over-prune synapses in vitro. However, genetic knockdown of type I IFN receptors reduces these phenotypes148, suggesting that increased inflammatory activity in the developing brain may drive microglia to excessively prune synapses and disrupt network refinement in the developing brain.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [148]
Genetic knockdown of type I IFN receptors reduces increased IFN signalling and over-pruning in T21 iPSC-derived microglia.
“However, genetic knockdown of type I IFN receptors reduces these phenotypes148, suggesting that increased inflammatory activity in the developing brain may drive microglia to excessively prune synapses and disrupt network refinement in the developing brain.”
From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [148]
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Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies
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Advances and Applications of Brain Organoids
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“I signaling, which causes increased synaptic pruning, and the microglia dysfunction and senescence can be rescued by inhibiting the IFN-I receptor [73].”
BackgroundIntegration of iPSC-Derived Microglia into Brain Organoids for Neurological Research
Mrza, M. A., He, J., & Wang, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063148 · Cited by 31 · see citing works
Glial interference: impact of type I interferon in neurodegenerative diseases
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Advanced in vitro models: Microglia in action
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“%) in COs [60–62].”
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“However, genetic knockdown of type I IFN receptors reduces these phenotypes 148 , suggesting that increased inflammatory activity in the developing brain may drive microglia to excessively prune synapses and disrupt network refinement in the developing brain.”
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Self-citationThe Breakthroughs and Caveats of Using Human Pluripotent Stem Cells in Modeling Alzheimer’s Disease
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STING in cancer immunoediting: Modeling tumor-immune dynamics throughout cancer development
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“Microglial chimeras from patients with Down syndrome have an elevated expression of IFNARs compared to controls, whereas inhibiting the IFNARs expression increases the ramification of DS microglia and rescues their synaptic pruning functions [47].”
BackgroundWu, Z., Zhou, Y., Hou, X., Liu, W., Yin, W., Wang, L., Cao, Y., Jiang, Z., Guo, Y., Chen, Q., et al. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.01.012 · Cited by 25 · see citing works
“iPSCs are pluripotent self-renewing cells that are reprogrammed from terminally differentiated somatic cells by introducing specific genes or molecules [21]. iPSCs have been widely used in the research fields of Parkinson ’ s disease, Alzheimer ’ s disease, and other nervous system diseases [31,32].”
MethodSelf-citationGalangin Rescues Alzheimer’s Amyloid-β Induced Mitophagy and Brain Organoid Growth Impairment
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Sting and p53 DNA repair pathways are compromised in Alzheimer’s disease
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“Impaired interferon responses would increase the risk of AD progression 138 and drive microglial dysfunction 139 .”
Research progress on interferon and cellular senescence
Wang, D., Chen, K., Wang, Z., Wu, H., & Li, Y. (2024) · The FASEB Journal · doi:10.1096/fj.202400808rr · Cited by 23 · see citing works
“223,224”
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“The pathological role of interferon signaling has been reported in a variety of neurological disorders including Alzheimer’s disease (AD), Down syndrome, traumatic brain injury (TBI), and stroke [3–8].”
BackgroundType I interferon signalling and interferon‐responsive microglia in health and disease
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“More recently, research on Down syndrome (DS) has shown that iPSC-derived microglia from DS patients transplanted into mouse brains display enhanced synaptic pruning activity, which in turn disrupts neuronal synaptic function (Jin et al., 2022).”
Chen, Z., Mao, Z., Tang, W., Shi, Y., Liu, J., & You, Y. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00517-1 · Cited by 21 · see citing works
“Even in patients with Down syndrome who usually progress to AD dementia in late stage of the disease, microglia also undergo cellular senescence characterized by elevated type I IFN signaling [244].”
The evolution of microglia replacement: A new paradigm for CNS disease therapy
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Self-citationEmerging roles for innate and adaptive immunity in tauopathies
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“42 Recent work further supports this model, showing that sustained IFN signaling in the aged brain primes microglia toward a chronic inflammatory phenotype that accelerates neurodegeneration, even without classic proteinopathies.”
Rise of the human-mouse chimeric brain models
Jiang, P., & Alam, M. M. (2022) · Cell Regeneration · doi:10.1186/s13619-022-00135-6 · Cited by 16 · see citing works
Self-citationThe role of interferon signaling in neurodegeneration and neuropsychiatric disorders
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Generation, interrogation, and future applications of microglia-containing brain organoids
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“The cGAS can be activated by cytosolic self-DNA derived from genome [19, 32], and the microglial cGAS-STING and IFN-I pathway is likely to play an important role in the neuropathology of AD patients [24–29].”
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“14e), consistent with impaired synaptic pruning 58 .”
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“Notably, recent studies have used iPSC-derived microglia and cortical organoids from Down syndrome patients and observed increased pruning and altered neuronal activity, high-lighting the importance of studying the interplay of multiple cell types in NDDs [28].”
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“(47) This shared feature suggests that increased type I IFN signaling in microglia may play a crucial role in the underlying mechanisms of AD, potentially linking the two conditions.”
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Chimeric brain models to study human glial-neuronal and macroglial-microglial interactions
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Human Immunodeficiency Virus (HIV-1) Targets Astrocytes via Cell-Free and Cell-Associated Infection
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“For instance, using microglial chimeric brains, a study has demonstrated that DS microglia exhibit excessive synaptic pruning during development and induce senescence when challenged with pathological tau, which is dependent on type-I interferon (IFN-I) signaling [86].”
Self-citationExpanding the neuroimmune research toolkit with in vivo brain organoid technologies
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“This is supported by findings demonstrating a role for γ-secretase in microglial state transitions [31] and studies implicating microglial interferon signalling in Down’s syndrome [71].”
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Neuroimmune Mechanisms of Neurodevelopmental Disorders
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iPSC-derived neural organoids in dementia research: Recent advances and future directions
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iPSCs-Derived Neurons and Brain Organoids from Patients
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“Additionally, Jin et al. observed that microglia in murine Down syndrome (DS) models had less convoluted morphologies than control microglia, indicating unique traits linked to DS pathology [39].”
InfluentialIn vitro senescence and senolytic functional assays
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Self-citation
- Authors
- Jin, M., Xu, R., Wang, L., Alam, M. M., Ma, Z., Zhu, S., Martini, A. C., Jadali, A., Bernabucci, M., Xie, P., Kwan, K. Y., Pang, Z. P., Head, E., Liu, Y., Hart, R. P., & Jiang, P.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- University of California, Irvine (US)
- Florida International University (US)
- Corresponding author
- Jiang, Peng
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2022-07
- Volume
- 29
- Issue
- 7
- Pages
- 1135-1153.e8
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC9345168
- OpenAlex
- W4284896135
- Cited by
- 174
- References
- 114
- Citations by year
- 2026: 41 · 2025: 49 · 2024: 48 · 2023: 26 · 2022: 10
- FWCI
- 12.55
- Type
- journal article
- Language
- en
- 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, 371 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)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (R01AG073779, P30AG066519)
- NINDS (R01NS102382, R01NS122108)
- National Institutes of Health
- BrightFocus Foundation (BFF17-0008)
- Florida State University
- Florida International University
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- Down syndrome, Alzheimer's disease, microglia, type I interferon signaling, IFNAR, microglial senescence, synaptic pruning, pathological tau, iPSC-derived brain organoids, chimeric mouse model, brain development
- MeSH terms
- Alzheimer Disease, Animals, Down Syndrome, Humans, Interferons, Amyloid beta-Peptides, Microglia, Mice, Induced Pluripotent Stem Cells
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