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Mouse Footpad Inoculation Model to Study Viral-Induced Neuroinflammatory Responses
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Basic Science and Pathogenesis.

Cassandra O Blew1, Michael R Duggan1, Dimitrios Tsitsipatis2

  • 1Laboratory of Behavioral Neuroscience, National Institute on Aging, Intramural Research Program, Baltimore, MD, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
PubMed
Summary
This summary is machine-generated.

Growth/differentiation factor-15 (GDF15) may increase dementia risk by altering macrophage functions. This protein influences key pathways, including interferon signaling and pyruvate metabolism, potentially contributing to dementia development.

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Area of Science:

  • Neuroscience
  • Immunology
  • Metabolomics

Background:

  • Elevated growth/differentiation factor-15 (GDF15) in plasma is linked to dementia development.
  • The precise role and biological mechanisms of GDF15 in dementia risk remain unclear.

Purpose of the Study:

  • To investigate the biological mechanisms by which GDF15 influences dementia incidence.
  • To determine if GDF15 is a valid risk factor for dementia.

Main Methods:

  • Macrophage proteomic changes were analyzed after exposure to recombinant human GDF15 (rhGDF15).
  • Pathway enrichment analyses identified biological pathways affected by rhGDF15.
  • These pathways were recreated in large cohorts (ARIC study) to assess associations with dementia risk.

Main Results:

  • rhGDF15 exposure upregulated metabolic pathways and downregulated inflammatory responses in macrophages.
  • 31 and 14 pathway composite scores were associated with midlife and late-life dementia risk, respectively.
  • Interferon signaling, pyruvate metabolism, and heme scavenging were key mediators linking GDF15 to dementia risk.

Conclusions:

  • GDF15's association with dementia risk is potentially mediated by its effects on macrophages and myeloid cells.
  • GDF15 may increase dementia risk by attenuating interferon signaling and heme scavenging while increasing pyruvate metabolism.