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

Abstract

Ageing population is causing increasing strain on healthcare systems worldwide, partially due to the growing prevalence of neurodegenerative diseases – a challenge that remains insufficiently addressed, notwithstanding active research. Trehalose, a mycose, has shown promise by its neuroprotective properties in various animal models. Trehalose has been shown to promote neuroprotection by inducing autophagy-mediated clearance of neurotoxic protein aggregates within the cell. However, the upstream mechanisms that initiate this autophagic cascade remain poorly understood, and it is unclear whether trehalose is synthesised endogenously, transported into the brain, or exerts its effects indirectly. While trehalase, the enzyme responsible for trehalose degradation, is well-defined in the human gut as a gastrointestinal enzyme, its presence in the human brain warrants careful investigation.

This study investigates the potential modulatory role of trehalase in trehalose-mediated neuroprotection by analysing two RNA-seq datasets obtained from human brain tissue. Hypothesis testing revealed a significant decline in trehalase expression in both patients with multiple sclerosis and aged individuals in comparison to control groups. Differential gene correlation analysis, integrated with biological pathway enrichment, demonstrated that trehalase-associated gene networks change with ageing, highlighting pathways related to autophagy, mitophagy, oxidative phosphorylation, and neurodegenerative conditions. Furthermore, cellular deconvolution analysis indicated that trehalase expression is associated with specific neural cell-type populations, suggesting a potential metabolic role or other functional link. Notably, trehalase expression showed consistent positive correlations with oligodendrocytes across brain regions, while negative correlations with neuronal proportions were detected in the hippocampus. A relatively strong co-expression profile with sirtuin 1, inducing longevity, further proposes that trehalase mediates neuroprotection.

These findings provide the supportive evidence that trehalase is expressed in the human brain and may has biologically meaningful role maintaining neural homeostasis and neuroprotection via proposed trehalase–trehalose axis in both neurons and glial cells. Therefore, these results position trehalase as a potential modulator of trehalose-related pathways in ageing and neurodegenerative conditions. Future research, integrating both trehalase and trehalose measurements in paired samples, is warranted to further examine functional dynamics of the trehalase–trehalose axis.