Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease
Open accessAbstract
Communication within the glial cell ecosystem is essential for neuronal and brain health 1-3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions 4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.
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Other inflammatory factors such as IL-3, IL-6, IL-18, TNFα, and MIF are involved in tau phosphorylation and/or truncation.
“Other inflammatory factors such as IL-3, IL-6, IL-18, tumor necrosis factor-α (TNFα), and macrophage migration inhibitory factor (MIF) are also found to be involved in tau phosphorylation and/or truncation [166–170].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [170]
Astrocyte-derived IL-3 binds to upregulated IL-3Rα in microglia, enhancing microglial migration toward Aβ deposits and clearance of Aβ aggregates.
“Astrocyte-derived IL-3 bound to the upregulated IL-3Rα in microglia, enhancing microglial migration toward Aβ deposits and the Aβ aggregates clearance.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [150]
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Fan, F., Joshi, P., Liu, X., Kotturu, S. K., Abiola, M., Liu, Q., & Lou, X. (2025) · doi:10.64898/2025.12.21.695860
- Authors
- McAlpine, C. S., Park, J., Griciuc, A., Kim, E., Choi, S. H., Iwamoto, Y., Kiss, M. G., Christie, K. A., Vinegoni, C., Poller, W. C., Mindur, J. E., Chan, C. T., He, S., Janssen, H., Wong, L. P., Downey, J., Singh, S., Anzai, A., Kahles, F., Jorfi, M., Feruglio, P. F., Sadreyev, R. I., Weissleder, R., Kleinstiver, B. P., Nahrendorf, M., Tanzi, R. E., & Swirski, F. K.
- Affiliations
- Harvard University (US)
- University of Verona (IT)
- Corresponding author
- Tanzi, Rudolph E.
- ORCID
- McAlpine, Cameron S.
- Park, Joseph
- Kim, Eunhee
- Choi, Se Hoon
- Iwamoto, Yoshiko
- Kiss, Máté G.
- Christie, Kathleen A.
- Vinegoni, Claudio
- Poller, Wolfram C.
- Mindur, John E.
- Chan, Christopher T.
- He, Shun
- Janssen, Henrike
- Wong, Lai Ping
- Downey, Jeffrey
- Singh, Sumnima
- Anzai, Atsushi
- Kahles, Florian
- Jorfi, Mehdi
- Sadreyev, Ruslan I.
- Weissleder, Ralph
- Kleinstiver, Benjamin P.
- Nahrendorf, Matthias
- Tanzi, Rudolph E.
- Swirski, Filip K.
- Venue
- Nature
- Published
- 2021-07-14
- Volume
- 595
- Issue
- 7869
- Pages
- 701-706
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8934148
- OpenAlex
- W3182356919
- Cited by
- 322
- References
- 61
- Citations by year
- 2026: 38 · 2025: 68 · 2024: 70 · 2023: 72 · 2022: 51 · 2021: 22
- FWCI
- 21.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (F31HL147364, R35HL135752, K99HL151750, R00HL151750, R35HL139598, P01HL131478, P01HL142494, R01HL158534)
- National Cancer Institute (R01CA158534, R00CA218870, R13CA135752)
- National Institute of General Medical Sciences (R35GM139598)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- interleukin-3, astrocytes, microglia, Alzheimer's disease, amyloid-beta clearance, tau clearance, CD123, microglial motility, cognitive decline, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Cell Communication, Cells, Cultured, Humans, Interleukin-3, Mice, Inbred C57BL, Microglia, Mice, Knockout, Mice, Neural Stem Cells
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