Deubiquitinating Enzymes in Alzheimer's Disease: From Protein Homeostasis to Diverse Pathological Processes

Alzheimer's disease (AD) is a neurodegenerative disorder involving multiple pathological processes, including amyloid-β (Aβ) accumulation, tau pathology, impaired autophagy, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction. Deubiquitinating enzymes (DUBs) reverse ubiquitination and regulate protein stability, degradation, and cellular signaling. Although studies of DUBs in AD have largely focused on Aβ metabolism and tau homeostasis, accumulating evidence implicates DUBs in a broader range of AD-related processes, including autophagy, neuroinflammation, mitochondrial function, and synaptic function. Several DUBs have also been implicated in more than one of these processes, although these effects have often been identified in different experimental models. In this review, we summarize current knowledge of DUBs in major AD-related pathological processes and discuss the mechanisms through which individual DUBs may influence different aspects of AD pathology. We also discuss the limitations of current studies and the potential and challenges of targeting DUBs in AD.