Lipid‐induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders

Neuropathic lysosomal storage disorders ( LSD s) present with activated pro‐inflammatory microglia. However, anti‐inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann–Pick disease type A ( NPA ). We establish that an NPA patient and the acid sphingomyelinase knockout ( ASM ko) mouse model show amoeboid microglia in neurodegeneration‐prone areas. In vivo microglia ablation worsens disease progression in ASM ko mice. We demonstrate the coexistence of different microglia phenotypes in ASM ko brains that produce cytokines or counteract neuronal death by clearing myelin debris. Overloading microglial lysosomes through myelin debris accumulation and sphingomyelin build‐up induces lysosomal damage and cathepsin B extracellular release by lysosomal exocytosis. Inhibition of cathepsin B prevents neuronal death and behavioural anomalies in ASM ko mice. Similar microglia phenotypes occur in a Niemann–Pick disease type C mouse model and patient. Our results show a protective function for microglia in LSD s and how this is corrupted by lipid lysosomal overload. Data indicate cathepsin B as a key molecule mediating neurodegeneration, opening research pathways for therapeutic targeting of LSD s and other demyelinating diseases.