Inflammatory proteostasis reprogramming creates a lysosomal bottleneck for microglial aggregate clearance

Efficient clearance of extracellular protein aggregates by microglia is essential for maintaining brain homeostasis and limiting the accumulation of pathological proteins during neurodegeneration. However, how inflammatory activation affects the ability of microglia to internalize and degrade these aggregates remains incompletely understood. Here, we show that lipopolysaccharide (LPS)-induced inflammatory activation impairs the degradation of extracellularly-acquired α-synuclein (α-Syn) and Tau aggregates while largely preserving their uptake. Mechanistically, Toll-like receptor 4 (TLR4) activation induces translational reprogramming and increases intracellular proteostatic demand, while inhibition of protein synthesis restores α-Syn degradation without preventing inflammatory Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Despite largely preserved canonical autophagic flux, inflammatory stimulation is associated with reduced expression of lysosomal proteins, including cathepsin D, suggesting insufficient lysosomal adaptation to increased intracellular demand. Consistent with this model, pharmacological activation of transcription factor EB (TFEB) restores aggregate degradation, indicating that the impairment can be overcome by enhancing lysosomal function. Supporting its potential relevance to human disease, microglial α-Syn deposits in brain tissue from patients with dementia with Lewy bodies show limited spatial association with cathepsin D-positive structures. Together, our findings identify a demand-driven lysosomal bottleneck through which inflammatory activation compromises aggregate degradation without substantially affecting uptake, highlighting lysosomal adaptation as a critical determinant of microglial aggregate clearance during neuroinflammation.