Cited by 386Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease

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Hur, Ji-Yeun, Frost, Georgia R., Wu, Xianzhong, Crump, Christina, Pan, Si Jia, Wong, Eitan, Barros, Marilia, Li, Thomas, Nie, Pengju, Zhai, Yujia, Wang, Jen Chyong, TCW, Julia, Guo, Lei, McKenzie, Andrew, Ming, Chen, Zhou, Xianxiao, Wang, Minghui, Sagi, Yotam, Renton, Alan E., Esposito, Bianca T., Kim, Yong, Sadleir, Katherine R., Trinh, Ivy, Rissman, Robert A., Vassar, Robert, Zhang, Bin, Johnson, Douglas S., Masliah, Eliezer, Greengard, Paul, Goate, Alison, Li, Yue-Ming·2020·Nature

DOI 10.1038/s41586-020-2681-2PMC PMC7919141

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Abstract

Innate immunity is associated with Alzheimer's disease 1, but the influence of immune activation on the production of amyloid-β is unknown 2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-β. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-β. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.

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Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19728391
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Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19728373
Additional file 8 of BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia
Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19728388
Additional file 4 of Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease
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Additional file 3 of Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease
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Additional file 7 of BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia
Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19728385
Additional file 1 of Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease
Munawara, U., Catanzaro, M., Xu, W., Tan, C., Hirokawa, K., Bosco, N., Dumoulin, D., Khalil, A., Larbi, A., Lévesque, S., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14821079
Additional file 5 of BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia
Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19728379
Additional file 2 of BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia
Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19728370
Additional file 2 of Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease
Munawara, U., Catanzaro, M., Xu, W., Tan, C., Hirokawa, K., Bosco, N., Dumoulin, D., Khalil, A., Larbi, A., Lévesque, S., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14821082
Additional file 1 of BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia
Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19728367
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Authors: Hur, J.-Y., Frost, G. R., Wu, X., Crump, C., Pan, S. J., Wong, E., Barros, M., Li, T., Nie, P., Zhai, Y., Wang, J. C., TCW, J., Guo, L., McKenzie, A., Ming, C., Zhou, X., Wang, M., Sagi, Y., Renton, A. E., Esposito, B. T., Kim, Y., Sadleir, K. R., Trinh, I., Rissman, R. A., Vassar, R., Zhang, B., Johnson, D. S., Masliah, E., Greengard, P., Goate, A., & Li, Y.-M.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Icahn School of Medicine at Mount Sinai (US)
Rockefeller University (US)
Northwestern University (US)
University of California San Diego (US)
Pfizer (United States) (US)
Corresponding author: Li, Yue-Ming
ORCID: Hur, Ji-Yeun
Frost, Georgia R.
Wong, Eitan
Barros, Marilia
Li, Thomas
Zhai, Yujia
TCW, Julia
Guo, Lei
McKenzie, Andrew
Ming, Chen
Zhou, Xianxiao
Wang, Minghui
Sagi, Yotam
Renton, Alan E.
Kim, Yong
Sadleir, Katherine R.
Trinh, Ivy
Rissman, Robert A.
Vassar, Robert
Zhang, Bin
Johnson, Douglas S.
Masliah, Eliezer
Greengard, Paul
Goate, Alison
Li, Yue-Ming
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2020-09-02
Volume: 586
Issue: 7831
Pages: 735-740
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-020-2681-2
PMC: PMC7919141
OpenAlex: W3082942379
Cited by: 382
References: 64
Citations by year: 2026: 53 · 2025: 51 · 2024: 53 · 2023: 68 · 2022: 77 · 2021: 65 · 2020: 15
FWCI: 34.14
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health (1s10od018522-01, 1s10od026880-01)
National Institute on Aging (R01AG057907, R01AG026660, U01AG046170, R01AG018440, R01AG006170, RF1AG057440, K01AG062683, RF1AG057593, R01AG061350, P30AG062429)
National Cancer Institute (P30CA008748)
National Institute of Neurological Disorders and Stroke (R01NS096275)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: IFITM3, gamma-secretase, Alzheimer's disease, amyloid-beta, innate immunity, neuroinflammation, inflammatory cytokines, presenilin, amyloid plaques, 5xFAD mice, late-onset Alzheimer's disease, aging, familial Alzheimer's disease
MeSH terms: Aged, 80 and over, Aging, Alzheimer Disease, Animals, Astrocytes, Disease Models, Animal, Female, Humans, Immunity, Innate, Inflammation, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Risk, Up-Regulation, Amyloid beta-Protein Precursor, RNA-Binding Proteins, Age of Onset, Catalytic Domain, Mice, Presenilin-1, Amyloid Precursor Protein Secretases, HEK293 Cells

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The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease

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