Dysregulated mRNA Translation in Alzheimer's Disease: Mechanisms, Therapeutic Opportunities, and Challenges for Clinical Translation.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a growing public health concern. Its core pathological features include cerebral amyloid-β deposition and tau aggregation. mRNA translation is a tightly regulated process essential for gene expression and protein synthesis. It plays critical roles in neural development, synaptogenesis, and synaptic plasticity. In recent years, dysregulated translational control has been recognized as an important pathogenic mechanism in several neurological diseases, including AD. This review provides an integrated overview of the biological basis and mechanisms of dysregulated mRNA translation in AD, including translation initiation and elongation, local synaptic translation, abnormalities in RNA-binding proteins and stress granules, tRNA dysregulation, and the effects of AD-related genetic factors on translational control. Beyond the classic mechanisms of protein aggregation, the onset and progression of AD are also accompanied by abnormal translational regulation, involving initiation, elongation, and local synaptic translation. A major feature of these abnormalities is the coexistence of suppressed global protein synthesis and selectively enhanced translation of certain disease-related mRNAs, involving the integrated stress response, eIF2α/eIF4E signaling, eEF2K/eEF2 pathway, and RNA-binding protein dysfunction. Translational dysregulation provides a new perspective for understanding the molecular pathology of AD and has prompted the exploration of interventions targeting key nodes in translational control. Strategies targeting the integrated stress response, cap-dependent translation initiation, eEF2K, and tau-RNA-binding protein interactions have shown potential to improve synaptic function and cognitive phenotypes in animal models, although their safety and clinical translatability require further evaluation. This review provides an up-to-date reference for understanding translation-centered mechanisms in AD and evaluating emerging therapeutic strategies targeting translational control.