Protein Modifications and Quality Control Systems Emerge as Key Therapeutic Targets for Alzheimer's Disease

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive dementia, memory loss, and severe cognitive decline, affecting over 55 million people globally. Current treatments offer symptomatic relief but fail to halt disease progression, largely due to a historical focus on single pathogenic mechanisms. The complex etiology of AD, involving multiple intertwined pathways, necessitates broader therapeutic strategies. This review explores the potential of targeting protein modifications and cellular quality control systems, which are increasingly recognized for their roles in AD pathogenesis, as novel and more comprehensive therapeutic avenues.

This paper presents a comprehensive review of existing literature on the role of protein modifications and cellular quality control systems in the pathogenesis of Alzheimer's disease (AD). The authors synthesized findings from various preclinical and clinical studies, examining how dysregulation in these systems contributes to neurodegeneration. The review aims to identify and discuss emerging therapeutic strategies that target these multifaceted pathways, providing a holistic perspective on potential disease-modifying interventions for AD.

The review synthesizes evidence demonstrating that aberrant protein modifications, such as phosphorylation, ubiquitination, and glycosylation, significantly contribute to the accumulation of toxic protein aggregates characteristic of Alzheimer's disease (AD). It highlights how impaired cellular quality control mechanisms, including the ubiquitin-proteasome system and autophagy-lysosomal pathway, fail to clear these misfolded proteins, exacerbating neuronal dysfunction and death. The authors emphasize that these interconnected processes are not merely consequences but active drivers of neurodegeneration.

The review concludes that targeting these protein modification and quality control pathways offers a promising, multi-faceted approach to developing disease-modifying therapies for AD, moving beyond single-target strategies. Furthermore, the paper discusses how restoring the balance of these systems could mitigate synaptic dysfunction and neuroinflammation, key pathological hallmarks of AD, suggesting a paradigm shift in therapeutic development.