DUBs in Alzheimer's disease: mechanisms and therapeutic implications

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid β protein (Aβ) and the hyper-phosphorylation of the microtubule-associated protein Tau. The ubiquitin-proteasome system (UPS) plays a pivotal role in determining the fate of proteins, and its dysregulation can contribute to the buildup of Aβ and Tau. Deubiquitinating enzymes (DUBs), working in conjunction with activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3), actively maintain the delicate balance of protein homeostasis. DUBs specifically remove ubiquitin tags from proteins marked for degradation, thereby averting their proteasomal breakdown. Several DUBs have demonstrated their capacity to regulate the levels of Aβ and Tau by modulating their degree of ubiquitination, underscoring their potential as therapeutic targets for AD. In this context, we present a comprehensive review of AD-associated DUBs and elucidate their physiological roles. Moreover, we delve into the current advancements in developing inhibitors targeting these DUBs, including the determination of cocrystal structures with their respective targets. Additionally, we assess the therapeutic efficacy of these inhibitors in AD, aiming to establish a theoretical foundation for future AD treatments.