Molecular Solution to the Paradox of Ancient Brain Preservation.

Brains decompose rapidly after death yet frequently survive in the archeological record, including >1300 cases of waterlogged, oxygen-poor graves in which the brain is the only preserved soft tissue amongst otherwise skeletonized remains. To address this paradox, we decayed mouse carcasses for six months in four burial regimes varying in water and oxygen availability, characterized the brain proteome by high-resolution liquid chromatography-tandem mass spectrometry using parallel data-dependent and -independent acquisition workflows at six post-mortem intervals, and modeled >1.26 million peptide-specific decay trajectories to identify decay-prone and -resistant sequences. Oxygen availability exerted the main control on molecular fate: oxic burials produced widespread protein loss, whereas wet, hypoxic conditions favored retention of a distinctive subset of decay-resistant peptides. These surviving sequences were structurally ordered, enriched in redox-active residues and in regions that bind metals and lipids, and bore modification patterns consistent with radical-mediated oxidative cross-linking rather than fragmentation. By linking intrinsic tissue chemistry and environmental context, our results move brain preservation from anomaly to expectation: resolving why brains outlast other soft tissues in waterlogged, oxygen-poor burials, and revealing that the molecular signatures of post-mortem peptide persistence closely mirror those of pathological protein stabilization in brain aging and neurodegeneration.