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Cited by 4Immune Response and InflammationAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

γ-Secretase fanning the fire of innate immunity

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Liu, Chenge, Nikain, Cyrus, Li, Yue-Ming·2023·Biochemical Society Transactions
DOI 10.1042/bst20221445PMC PMC11212119
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Abstract

Innate immunity is the first line of defense against pathogens, alerting the individual cell and surrounding area to respond to this potential invasion. γ-secretase is a transmembrane protease complex that plays an intricate role in nearly every stage of this innate immune response. Through regulation of pattern recognition receptors (PRR) such as TREM2 and RAGE γ-secretase can modulate pathogen recognition. γ-secretase can act on cytokine receptors such as IFNαR2 and CSF1R to dampen their signaling capacity. While γ-secretase-mediated regulated intramembrane proteolysis (RIP) can further moderate innate immune responses through downstream signaling pathways. Furthermore, γ-secretase has also been shown to be regulated by the innate immune system through cytokine signaling and γ-secretase modulatory proteins such as IFITM3 and Hif-1α. This review article gives an overview of how γ-secretase is implicated in innate immunity and the maintenance of its responses through potentially positive and negative feedback loops.

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  • FAD-linked mutations in PSEN1/PSEN2 promote production of pathogenic Aβ42 peptides from APP.

    “Mutations in either presenilin 1 or 2 ( PSEN1/PSEN2 ) genes, the proteolytic component of the γ -secretase complex, promote the production of pathogenic A β 42 peptides from amyloid precursor protein (APP) protein.”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [13]

    The Introduction (page unavailable) says that PS1 and PS2 mutations are implicated in familial Alzheimer’s disease and that APP is the substrate from which γ-secretase produces Aβ. It does not say that those mutations promote production specifically of Aβ42 from APP. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • γ-secretase processes immune-relevant substrates including TREM2, RAGE and several cytokine receptors.

    “Beyond its role in APP processing, γ -secretase also processes a broad repertoire of immune-relevant substrates including triggering receptor expressed on myeloid cells 2 (TREM2), receptor for advanced glycation end products (RAGE) and several cytokine receptors [13].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [13]

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Cited by

Sorted by citations

Authors
Liu, C., Nikain, C., & Li, Y.-M.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Li, Yue-Ming
ORCID
Venue
Biochemical Society Transactions
Publisher
Portland Press Ltd.
Published
2023-07-14
Volume
51
Issue
4
Pages
1597-1610
ISSN
  • 0300-5127 (ISSN-L)
  • 1470-8752
DOI
10.1042/bst20221445
PMC
PMC11212119
OpenAlex
W4384343270
Cited by
4
References
19
Citations by year
2026: 4
FWCI
0.11
Type
journal article
Language
en
Open access
Locations
  • Biochemical Society Transactions (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • MetLife Foundation
  • Memorial Sloan-Kettering Cancer Center (CA008748, P30 CA008748)
  • Cure Alzheimer's Fund
  • Edward N. and Della L. Thome Memorial Foundation
  • Alzheimer's Research Trust
  • National Institutes of Health (CA008748)
  • National Institute on Aging (RF1AG057593, R01AG061350, R01AG080684)
  • National Cancer Institute (P30CA008748)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
gamma-secretase, innate immunity, regulated intramembrane proteolysis, pattern recognition receptors, TREM2, RAGE, CSF1R, cytokine signaling, IFITM3, HIF-1α, feedback loops, pathogen recognition
MeSH terms
Immunity, Innate, Signal Transduction, Amyloid Precursor Protein Secretases

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