Journal Article

DZNE-2025-01359

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Enhancing Tyro3 signaling ameliorates IL-1β production through STAT1 in Alzheimer's disease models.

Ravichandran, K. A. (First author)DZNE* ; Brosseron, F.DZNE* ; McManus, R. M.DZNE* ; Ising, C. ; Görgen, S. ; Schmidt, S. V. ; Santarelli, F. ; Lee, S. Y. ; Jung, H. ; Chung, W.-S. ; Kim, C. H. ; Ruiz Laza, A. ; Ruiz de Almodóvar, C. ; Ramirez, A.Extern* ; Latz, E.DZNE* ; Heneka, M. T. (Last author)DZNE*

2025
Oxford University Press Tokyo

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Please use a persistent id in citations: doi:10.1093/jleuko/qiaf157

Abstract: Neuroinflammation plays a vital role in determining the trajectory of Alzheimer's disease (AD) progression. In the AD brain, microglial exposure to pathological amyloid β (Aβ42) and tau peptide aggregates results in an NLRP3 inflammasome-activated proinflammatory response that ranges from mild to severe. Recently we have shown that dementia subjects with higher levels of soluble TAM receptors Tyro3 and AXL in the cerebrospinal fluid indicated cognitive protection. The molecular mechanism for this protective effect of TAM receptors is unknown. Here, we identified a beneficial role of TAM receptors using Tyro3-overexpressing (Tyro3OE) and Axl-overexpressing THP-1 cells. In the Tyro3OE cells, the levels of the proinflammatory cytokine IL-1β were markedly decreased in the AD microenvironment (tau + Aβ42) and the classical NLRP3 inflammasome model (lipopolysaccharide [LPS] + nigericin) in comparison with the control cells. This was mediated by increased STAT1 phosphorylation and reduced IL-1β transcription enhancer C-EBP-β in Tyro3OE cells. The use of the JAK1/2 inhibitor ruxolitinib reduced the phosphorylation of STAT1, leading to a partial restoration of IL-1β in the Tyro3OE cells. Last, we found a significantly reduced IL-1β in the brains of AD mice that has activated TAM signaling through Gas6-α-Aβ lentiviral injection. In summary, TAM receptor Tyro3 overexpression decreased AD-associated IL-1β release from macrophages thereby uncovering a potential beneficial role for TAM receptors during neuroinflammation in AD.

Keyword(s): Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Interleukin-1beta: biosynthesis (MeSH) ; Interleukin-1beta: metabolism (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Signal Transduction (MeSH) ; Disease Models, Animal (MeSH) ; STAT1 Transcription Factor: metabolism (MeSH) ; Mice (MeSH) ; Receptor Protein-Tyrosine Kinases: metabolism (MeSH) ; Receptor Protein-Tyrosine Kinases: genetics (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Inflammasomes: metabolism (MeSH) ; THP-1 Cells (MeSH) ; Proto-Oncogene Proteins: metabolism (MeSH) ; Phosphorylation (MeSH) ; Axl Receptor Tyrosine Kinase (MeSH) ; Male (MeSH) ; Mice, Inbred C57BL (MeSH) ; Nitriles (MeSH) ; Mice, Transgenic (MeSH) ; AD ; Alzheimer’s disease ; IL-1β ; NLRP3 ; TAM receptors ; Interleukin-1beta ; STAT1 Transcription Factor ; Receptor Protein-Tyrosine Kinases ; Amyloid beta-Peptides ; Inflammasomes ; Proto-Oncogene Proteins ; Axl Receptor Tyrosine Kinase ; Tyro3 protein, mouse ; TYRO3 protein, human ; Nitriles

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Contributing Institute(s):

1. Neuroinflammation, Biomarker (AG Heneka)
2. Translational Neuroimmunology (AG McManus)
3. Innate Immunity in Neurodegeneration (AG Latz)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)
3. 351 - Brain Function (POF4-351) (POF4-351)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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