Recent advances in glycobiology have revealed that aberrant glycosylation modifications and the accumulation of advanced glycation end products are key pathways driving neural aging and impeding regeneration. This review focuses on the mechanisms by which abnormal glycosylation and advanced glycation end products drive neurodegeneration, as well as their potential applications. Evidence exists that abnormal N-linked glycosylation disrupts synaptic protein trafficking and mitochondrial dynamics, while O-GlcNAcylation directly impairs synaptic plasticity through dysregulated phosphorylation of tau protein and synapsin. Concurrently, advanced glycation end products crosslink with extracellular matrix components and activate receptor for advanced glycation end products-dependent neuroinflammatory cascades, thereby establishing a self-perpetuating cycle of neural dysfunction. Critically, this review identifies three convergent mechanisms: (1) Glycosylation-dependent proteostasis disruption exacerbates the aggregation of amyloid-β and α-synuclein; (2) advanced glycation end products-induced oxidative stress accelerates the imbalance of mitochondrial fission and fusion; and (3) synergistic glycation damage inhibits axonal regeneration by impairing the dynamic stability of growth cones. Emerging intervention strategies show promising potential, proposing dual approaches that target aberrant glycosylation and the accumulation of advanced glycation end products. Clinical translation faces multiple challenges, including the precision of tissue-specific delivery of glycosylation modifiers and long-term safety concerns. This narrative review establishes glycation as a core regulatory mechanism in neural aging while providing a theoretical framework for developing pathology-specific glycosylation therapies.
Zhao et al. (Thu,) studied this question.