Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques
Open accessAbstract
The principal signals that drive memory and cognitive impairment in Alzheimer's disease (AD) remain elusive. Here, we revealed brain-wide cellular reactions to type I interferon (IFN-I), an innate immune cytokine aberrantly elicited by amyloid β plaques, and examined their role in cognition and neuropathology relevant to AD in a murine amyloidosis model. Using a fate-mapping reporter system to track cellular responses to IFN-I, we detected robust, Aβ-pathology-dependent IFN-I activation in microglia and other cell types. Long-term blockade of IFN-I receptor (IFNAR) rescued both memory and synaptic deficits and resulted in reduced microgliosis, inflammation, and neuritic pathology. Microglia-specific Ifnar1 deletion attenuated the loss of post-synaptic terminals by selective engulfment, whereas neural Ifnar1 deletion restored pre-synaptic terminals and decreased plaque accumulation. Overall, IFN-I signaling represents a critical module within the neuroinflammatory network of AD and prompts concerted cellular states that are detrimental to memory and cognition.
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In APP/PS1 mice and 5xFAD mice, loss of type I IFN signaling is protective, ameliorating Aβ pathology and attenuating neurotoxicity, synapse loss, and microglial activation.
“In APP/PS1 mice and 5xFAD mice, loss of type I IFN signaling is protective ameliorating the Aβ pathology and attenuating neurotoxicity, synapse loss, and microglial activation.”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [78]
The Results sections on IFN-I blockade report restored excitatory synapse markers, reduced microglial activation, and partial reductions in neuritic pathology in 5XFAD mice. But blockade did not reduce Aβ plaque load; only neural-cell-specific Ifnar1 deletion did. The paper does not report these protective effects as findings from its own APP/PS1 experiments, so the claim overgeneralizes across models and forms of IFN-I loss. (LLM, conf=0.90)
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 [78]
The Results section ('IFN-I blockade rescues memory and synaptic deficits'; page not provided) reports restored memory in an amyloid-plaque mouse model after IFN-I receptor blockade. Other Results passages link IFN-I signaling to neuroinflammation and neuritic pathology, but the human AD evidence is observational; the paper does not demonstrate that IFN-I signaling is essential for cognitive impairment in people with AD. (LLM, conf=0.85)
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Research progress on interferon and cellular senescence
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Araya, P., Niemeyer, B., Schade, K., Dunn, L. N., Waugh, K., Busquet, N., Brindley, C., Brown, C., Winkler, C., Lyford, H. R., et al. (2025) · iScience · doi:10.1016/j.isci.2025.113130 · Cited by 7 · see citing works
“…we observed in cognitive function associated with DS-AD are consistent with 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.”
Non-invasive in vivo imaging of brain and retinal microglia in neurodegenerative diseases
Etebar, F., Harkin, D. G., White, A. R., & Dando, S. J. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1355557 · Cited by 7 · see citing works
- Authors
- Roy, E. R., Chiu, G., Li, S., Propson, N. E., Kanchi, R., Wang, B., Coarfa, C., Zheng, H., & Cao, W.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Cao, Wei
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2022-05
- Volume
- 55
- Issue
- 5
- Pages
- 879-894.e6
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC9109419
- OpenAlex
- W4224216596
- Cited by
- 236
- References
- 22
- Citations by year
- 2026: 59 · 2025: 72 · 2024: 55 · 2023: 32 · 2022: 16 · 2021: 2
- FWCI
- 15.62
- 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, 374 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
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- National Institute on Aging (RF1AG057587, RF1AG020670, RF1AG062257, R01AG020670, R01AG074283)
- National Cancer Institute (P30CA125123)
- National Institute of Neurological Disorders and Stroke (RF1NS093652, R01NS093652)
- National Institute of Environmental Health Sciences (P30ES030285, P42ES027725)
- National Institute on Minority Health and Health Disparities (P50MD015496)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Keywords
- type I interferon signaling, Alzheimer's disease, amyloid plaques, microglia, IFNAR1, memory impairment, neuroinflammation, synaptic deficits, microglial activation, neuritic plaques, cognitive impairment
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Immunity, Innate, Interferon Type I, Memory Disorders, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Microglia, Mice, Plaque, Amyloid
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