Inflammatory proteostasis reprogramming creates a lysosomal bottleneck for microglial aggregate clearance

LPS-driven inflammatory activation in microglia impairs degradation of extracellularly acquired α-Synuclein and Tau aggregates while largely preserving their uptake, linked to reduced lysosomal protein expression.

• Why it matters: Neuroinflammation may hinder microglial clearance of pathological protein aggregates, but the specific step affected and the underlying proteostasis mechanism were unclear.
• What they did: Microglia were stimulated with lipopolysaccharide (LPS) to activate TLR4, which increased proteostatic demand via translational reprogramming; protein synthesis inhibition restored α-Syn degradation without blocking NF-κB activation.
• The result: Despite largely preserved canonical autophagic flux, lysosomal proteins including cathepsin D were reduced, and TFEB activation restored aggregate degradation; patient dementia with Lewy bodies showed limited spatial association between microglial α-Syn deposits and cathepsin D-positive structures.

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