Trehalase–trehalose axis in the human brain: A potential modulator of neuroprotection and neurodegeneration

Trehalase, the primary enzyme responsible for the degradation of gastrointestinal trehalose ("mushroom sugar"), is well-characterised in the human gut, but has not been conclusively identified in the human brain. Trehalose itself has shown promise in neuroprotection through diverse molecular mechanisms, including the autophagy-driven clearance of cellular debris and neurotoxic aggregates. However, the mechanisms activating trehalose and its integration into human central nervous system processes remain elusive. To investigate the modulatory role of trehalase in the trehalose-mediated neuroprotection, we analysed two independent RNA-seq datasets derived from post-mortem human brain tissue. Hypothesis testing of age- and multiple sclerosis-associated changes in trehalase gene expression revealed significant decrease in both aged donors and patients with multiple sclerosis compared to controls. Differential gene correlation analysis combined with pathway enrichment showed that trehalase-associated gene networks shift according to bimodal age segmentation, implicating pathways related to autophagy, mitophagy, oxidative phosphorylation, and neurodegeneration. Moreover, trehalase expression correlated positively with oligodendrocyte proportions in many brain regions and negatively with neuronal proportions in the hippocampus, suggesting cell-type-specificity. A robust positive association with sirtuin 1 expression further links trehalase to established neuroprotection. These results provide the first direct evidence of trehalase expression in the human brain and suggest that the trehalase-trehalose axis may function as a mediator of cellular homeostasis and neuroprotection in neurons and glia. Our results position trehalase as a candidate biomarker and modulator of trehalose-linked pathways in ageing and neurodegeneration, warranting future studies integrating both trehalase and trehalose profiling in paired samples.