| First Author | L??pez-L??pez V | Year | 2026 |
| Journal | J Neuroinflammation | Volume | 23 |
| Issue | 1 | PubMed ID | 42083037 |
| Mgi Jnum | J:388158 | Mgi Id | MGI:8355758 |
| Doi | 10.1186/s12974-026-03840-0 | Citation | Lopez-Lopez V, et al. (2026) Sex-dependent interferon signaling contributes to female-biased vulnerability in Alzheimer's disease. J Neuroinflammation |
| abstractText | Alzheimer's disease (AD) disproportionately affects women, yet the biological basis of this sex bias remains unclear. Here, we identify sex-dependent interferon signaling as a contributor to this disparity. Transcriptomic profiling of postmortem AD tissue and APP/PS1 mice revealed preferential enrichment of interferon-responsive gene programs in females. In APP/PS1 mice, heightened interferon responses were associated with increased neurodegenerative features, and single-cell transcriptomic analyses identified microglia as a major cellular compartment engaging interferon responses. To test causality, we manipulated interferon signaling in vivo. Acute systemic interferon activation promoted AD-like neuropathological alterations. Genetic amplification of interferon signaling in microglia exacerbated neuroinflammatory and neurodegenerative features in APP/PS1 mice, whereas pharmacological inhibition through cGAS-STING blockade suppressed interferon responses, reduced neuropathology, and preserved cognitive performance in female APP/PS1 mice. Together, these findings identify microglial interferon signaling as a modifiable contributor to AD-associated neuropathology and suggest a neuroimmune mechanism underlying the increased vulnerability of females to the disease. |
