Advanced Glycation End Products and Hydrogen Sulfide in Alzheimer's Disease: Molecular Mechanisms and Emerging Therapeutic Targets

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β (Aβ) plaque deposition, and neurofibrillary tangle formation. Emerging evidence highlights the pivotal role of advanced glycation end products (AGEs) and their receptor (RAGE) in AD pathogenesis. AGEs accumulate during aging, diabetes, and metabolic disorders through nonenzymatic glycation and glycoxidation under oxidative stress. Their interaction with RAGE activates the NF-κB signaling pathway, promoting oxidative stress, mitochondrial dysfunction, blood–brain barrier (BBB) disruption, and chronic neuroinflammation. This AGE–RAGE axis enhances the production of pro-inflammatory mediators, including TNF-α, IL-6, MCP-1, VCAM-1, and reactive oxygen and nitrogen species (ROS/RNS), while accelerating amyloid-β aggregation, tau hyperphosphorylation, impaired mitophagy, mitochondrial dysfunction, cerebrovascular injury, and reduced Aβ clearance, ultimately contributing to neuronal degeneration. Hydrogen sulfide (H₂S), an endogenous gaseous signaling molecule synthesized by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), has emerged as a promising neuroprotective agent in AD. H₂S activates the Nrf2 antioxidant pathway, enhances glutathione synthesis, reduces oxidative stress, preserves mitochondrial integrity, supports long-term potentiation, modulates neurotransmission, attenuates Aβ-induced neurotoxicity, and suppresses neuroinflammation. Reduced H₂S levels are closely associated with cognitive impairment in AD. Overall, the AGE–RAGE axis plays a central role in AD progression, whereas H₂S acts as a protective modulator by targeting multiple pathogenic mechanisms. Therapeutic strategies that inhibit AGE–RAGE signaling while enhancing endogenous H₂S production may offer a promising approach to slowing Alzheimer's disease progression.