LLPS Inflammasome Metabo-Proteostatic Failure Axis in AD: Mechanistic and Translational Insights

Alzheimer's Disease (AD) is a multifactorial and progressive neurodegenerative disorder for which effective disease-modifying therapies to halt or slow disease progression remain limited. Current pathogenic models primarily focus on the accumulation of amyloid-β (Aβ) and tau proteins; however, these do not fully explain the extensive neuroinflammation, metabolic dysfunction, and impaired protein homeostasis observed in affected individuals. Recent evidence suggests that liquid-liquid phase separation (LLPS) can represent an important biophysical mechanism linking cellular stress, protein aggregation, innate immune activation, and metabolic imbalance in AD. Emerging studies indicate that dysregulated LLPS of tau and inflammasome components, particularly NLRP3, may promote the formation of stable and persistent condensates that amplify inflammatory signalling, impair autophagosome-lysosome function, and disrupt mitochondrial activity. However, direct evidence supporting these mechanisms specifically in AD remains limited, and several findings are derived from related experimental systems. In addition, ongoing metabolic stress-including depletion of NAD⁺ and ATP, oxidative damage, and mitochondrial dysfunction can further reinforce these pathological processes, contributing to a self-sustaining cycle of inflammation and metabolic imbalance. Collectively, these observations suggest that AD may involve dysfunction of interconnected cellular networks rather than solely the accumulation of toxic proteins. Nevertheless, this framework remains partly hypothesis-driven and requires further validation. Targeting LLPS dynamics, limiting chronic inflammasome activation, and restoring metabolic balance can represent promising, yet still emerging, therapeutic strategies.