Inflammation in the Niemann‐Pick type‐C brain

Niemann‐Pick Type‐C (NPC) disease is a fatal neurodegenerative disorder characterized by cholesterol accumulation in late endosomes/lysosomes. Microglia are resident immune cells of the central nervous system, which upon activation secrete potentially neurotoxic molecules such as tumor necrosis factor‐alpha (TNF‐α). Inappropriate activation of microglia has been implicated in several neurodegenerative disorders including NPC disease. We hypothesize that microglia play a primary role in neurodegeneration in NPC disease. To test this hypothesis, primary glia and microglia cultures were prepared from Npc1‐/‐ mice. Filipin staining of unesterified cholesterol shows that NPC1‐deficient microglia accumulate cholesterol. Additionally, treatment of wild‐type microglia with U18666A, a compound which mimics the cholesterol accumulation in NPC disease, causes microglia to assume an activated morphology. The TNF‐α content of conditioned media from Npc1‐/‐ glia was also higher than that of Npc1+/+ glia. Taken together, these results suggest that cholesterol accumulation activates microglia and increases the secretion of potentially toxic molecules, such as TNF‐α. Furthermore, elevated levels of TNF‐Receptor‐1, the TNF‐α receptor involved in apoptosis, were observed in Npc1‐/‐ brain regions such as the cerebellum. We also found that elimination of the Fc‐receptor common gamma chain, required for antibody‐based autoimmunity, in Npc1‐/‐ mice did not improve the clinical outcome of the disease. This observation is consistent with the idea that cholesterol accumulation causes microglial dysfunction, rather than the production of autoantibodies leading to an autoimmune response. Research Support: NSERC and CIHR