Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2025 Apr;22(3):e00482.
doi: 10.1016/j.neurot.2024.e00482. Epub 2024 Nov 8.

From defense to disease: IFITM3 in immunity and Alzheimer's disease

Zoe Kehs  1 , Abigail C Cross  2 , Yue-Ming Li  3
Affiliations
Review

From defense to disease: IFITM3 in immunity and Alzheimer's disease

Zoe Kehs et al. Neurotherapeutics. 2025 Apr.

Abstract

Innate immunity protein interferon induced transmembrane protein 3 (IFITM3) is a transmembrane protein that has a wide array of functions, including in viral infections, Alzheimer's Disease (AD), and cancer. As an interferon stimulated gene (ISG), IFITM3's expression is upregulated by type-I, II, and III interferons. Moreover, the antiviral activity of IFITM3 is modulated by post-translational modifications. IFITM3 functions in innate immunity to disrupt viral fusion and entry to the plasma membrane as well as prevent viral escape from endosomes. As a γ-secretase modulatory protein, IFITM3 distinctly modulates the processing of amyloid precursor protein (APP) to generate amyloid beta peptides (Aβ) and Notch1 cleavages. Increased IFITM3 expression, which can result from aging, cytokine activation, inflammation, and infection, can lead to an upregulation of γ-secretase for Aβ production that causes a risk of AD. Therefore, the prevention of IFITM3 upregulation has potential in the development of novel therapies for the treatment of AD.

Keywords: Amyloid; Infection; Inflammation; Innate immunity; Neuroimmunology; γ-Secretase.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yue-Ming Li reports a relationship with Memorial Sloan Kettering Cancer Center that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Purported topology of IFITM3. Current evidence supports an extracellular C-terminus and intracellular N-terminus along with an intramembrane amphipathic α-helix (AAH). Created using Biorender.com.
Fig. 2
Fig. 2
IFITM3 in the AD brain. IFITM3 modulates γ-secretase's cleavage of APP. In the AD brain, increased IFITM3 expression can lead to an increased ratio of Aβ42:Aβ40. Created using Biorender.com.
Fig. 3
Fig. 3
Roles of IFITM3 in defense and disease. IFITM3 inhibits both viral fusion to plasma membrane as well as viral escape from endosomes. IFITM3 modulates γ-secretase. Increased IFITM3 expression leads to an increase of Aβ42, which is aggregation prone. Amyloid plaques, in the antimicrobial hypothesis of AD, trap pathogens. These plaques also lead to microglial activation and eventual cytokine release which results in stimulation of IFITM3. Created using Biorender.com.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Long J.M., Holtzman D.M. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. 2019;179(2):312–339. - PMC - PubMed
    1. Kinney J.W., Bemiller S.M., Murtishaw A.S., Leisgang A.M., Salazar A.M., Lamb B.T. Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y) 2018;4:575–590. - PMC - PubMed
    1. Heneka M.T., Carson M.J., Khoury J.E., Landreth G.E., Brosseron F., Feinstein D.L., et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015;14(4):388–405. - PMC - PubMed
    1. Bailey C.C., Zhong G., Huang I.C., Farzan M. IFITM-family proteins: the cell's first line of antiviral defense. Annu Rev Virol. 2014;1:261–283. - PMC - PubMed
    1. Hur J.Y., Frost G.R., Wu X., Crump C., Pan S.J., Wong E., et al. The innate immunity protein IFITM3 modulates gamma-secretase in Alzheimer's disease. Nature. 2020;586(7831):735–740. - PMC - PubMed

MeSH terms