Approximately 70 lysosomal storage diseases are currently known, resulting from 
mutations in genes encoding lysosomal enzymes and membrane proteins. Defects in 
lysosomal enzymes that hydrolyze sphingolipids have been relatively well 
studied. Gaucher disease is caused by the loss of activity of 
glucocerebrosidase, leading to accumulation of glucosylceramide. Gaucher disease 
exhibits a number of subtypes, with types 2 and 3 showing significant 
neuropathology. Sandhoff disease results from the defective activity of 
β-hexosaminidase, leading to accumulation of ganglioside GM2. Niemann-Pick type 
C disease is primarily caused by the loss of activity of the lysosomal membrane 
protein, NPC1, leading to storage of cholesterol and sphingosine. All three 
disorders display significant neuropathology, accompanied by neuroinflammation. 
It is commonly assumed that neuroinflammation is the result of infiltration of 
monocyte-derived macrophages into the brain; for instance, cells resembling 
lipid-engorged macrophages ('Gaucher cells') have been observed in the brain of 
Gaucher disease patients. We now review the evidence that inflammatory 
macrophages are recruited into the brain in these diseases and then go on to 
provide some experimental data that, at least in the three mouse models tested, 
monocyte-derived macrophages do not appear to infiltrate the brain. Resident 
microglia, which are phenotypically distinct from infiltrating macrophages, are 
the only myeloid population present in significant numbers within the brain 
parenchyma in these authentic mouse models, even during the late symptomatic 
stages of disease when there is substantial neuroinflammation. OPEN SCIENCE 
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Special Issue "Lysosomal Storage Disorders".