Niemann-Pick Type C (NPC) disease is a rare and fatal neurovisceral storage disorder, which has no effective treatment. The pathological hallmark of NPC is accumulation of cholesterol and other lipids in the endosomal-lysosomal systems. Neurodegeneration is a common feature of the disease, and in most cases, dysfunction of the CNS is the final cause of death. The mechanisms underlying neurodegeneration are currently unknown; however, accumulating evidence indicates that NPC may share some common pathological mechanisms with Alzheimer's disease (AD). In particular, inflammation in CNS plays important roles in several neurodegenerative diseases, including AD, and our preliminary results showed that, in Npcl- /- mice, which exhibit many pathological features of the human NPC disease, activation of microglia occurred early during postnatal development, before evident signs of neurodegeneration. Furthermore, we also observed that treatment with an anti-inflammatory agent reduced microglial activation, demyelination, and neurodegeneration in Npcl-/- mice. The proposed studies will therefore test the hypothesis that microglial activation caused directly by intrinsic changes in microglia or indirectly by axonal degeneration, facilitates the propagation and progression of neurodegeneration in NPC disease. The following questions will be specifically addressed: 1) Is activation of microglia region specific? Does microglial activation precede neurodegeneration during postnatal development? 2) Do microglia from Npcl-/- mice produce neuronal damage to normal neuronal preparations from wild-type mice? Can suppression of microglia and cytokines reduce neurodegeneration in vitro? 3) Can anti-inflammation treatment reduce microglia activation, demyelination, and neurodegeneration in Npcl-/- mice in vivo? These studies will combine several approaches, using dissociated cell cultures, cultured brain tissue slices, and in vivo studies. Through investigating the roles of glia-mediated inflammation in NPC, the proposed studies will not only advance our understanding of the mechanisms underlying neurodegeneration in this disease but also help to reveal more general mechanisms underlying CNS degeneration. Finally, because microglia activation has also been implicated in the mechanisms underlying several neurodegenerative diseases, our proposal could lead to significant advances in the treatment of these diseases as well.
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