Protein persulfidation: The missing link in Alzheimer's disease defense mechanisms

Despite decades of research dominated by the amyloid-beta hypothesis, clinical treatment of Alzheimer's disease (AD) has yet to achieve a decisive breakthrough. This editorial advances an alternative pathological paradigm: the collapse of endogenous hydrogen sulfide (H₂S) signaling represents a central failure point in the brain's intrinsic defense mechanisms against AD. We dissect the molecular cascade triggered by cystathionine γ-lyase (CSE) deficiency, focusing on how reduced persulfidation of glycogen synthase kinase 3β (GSK3β) directly promotes Tau hyperphosphorylation and subsequent neuronal injury. A critical message of this commentary is the need to dispel the oversimplified notion that sulfide supplementation alone can confer neuroprotection. Because H₂S works within a narrow therapeutic window and has complex hormetic effects, untargeted dietary or environmental exposure cannot match the spatiotemporal precision of endogenous signaling. Instead, it may increase the risk of toxicity. By integrating analyses of transsulfuration metabolism, mitochondrial function, and nutritional status, we propose a precision medicine framework centered on brain-targeted delivery technologies and metabolic correction strategies to selectively restore compromised H₂S signaling networks. This conceptual shift marks a new direction in AD research, shifting the focus from clearing toxic protein aggregates to restoring endogenous neuronal resilience.