Aged AG129 mice support the generation of highly virulent novel mouse-adapted DENV (1-4) viruses exhibiting neuropathogenesis and high lethality

•Aged and old (IFN α/β/γ R-/-) deficient AG129 mice are highly susceptible to DENV 1-4 serotypes infection and supports rapid adaptation.•The adapted DENV-1-4 serotypes viruses resulted in elicitation of neurovirulence, a rare yet important clinical manifestation in severe Dengue infection in humans.•Extensive characterization of the age-adapted DENV 1-4 mouse strains demonstrated significant alteration of endothelial dysfunction, elevated TNF-α and INF-γ despite of the fact that the AG129 are deficient of IFN α/β/γ receptors.•The model is highly suitable for rapid screening of biotherapautics and anti-viral drugs against severe form of Dengue infection. Dengue virus infection in humans ranges from asymptomatic infection to severe infection, with ∼2.5 % overall disease fatality rate. Evidence of neurological manifestations is seen in the severe form of the disease, which might be due to the direct invasion of the viruses into the CNS system but is poorly understood. In this study, we demonstrated that the aged AG129 mice are highly susceptible to dengue serotypes 1–4, and following the adaptation, this resulted in the generation of neurovirulent strains that showed enhanced replication, aggravated disease severity, increased neuropathogenesis, and high lethality in both adult and aged AG129 mice. The infected mice had endothelial dysfunction, elicited pro-inflammatory cytokine responses, and exhibited 100 % mortality. Further analysis revealed that aged-adapted DENV strains induced measurable alterations in TLR expression in the aged mice as compared to the adult mice. In addition, metabolomics analysis of the serum samples from the infected adult mice revealed dysregulation of 18 metabolites and upregulation of 6-keto-prostaglandin F1 alpha, phosphocreatine, and taurocholic acid. These metabolites may serve as key biomarkers to decipher and comprehend the severity of dengue-associated severe neuro-pathogenesis.