Cholesterol dyshomeostasis compromises microglial physiological functions in a mouse model of Niemann Pick type C disease.

The Niemann-Pick type C (NPCD) disease is a lysosomal storage disorder characterised by the accumulation of cholesterol and glycosphingolipids in the endosomal/lysosomal compartments. The dyshomeostasis of intracellular cholesterol leads to a diffuse and progressive neuroinflammation and neurodegeneration, particularly affecting Purkinje cells (PCs). We recently demonstrated the presence of subtle defects in cerebellar morphogenesis of Npc1-deficient mice, including dysmyelination, a derangement of synaptic connectivity on PCs and a decreased number of granule neurons. These defects occur during the second postnatal week of age and are associated to anomalies in Shh signaling and reception at the primary cilium. We now hypothesize that cholesterol dyshomeostasis affects the acquisition of an appropriate maturation profile by microglia and/or astrocytes, thus contributing to neural alterations of NPCD. In particular, we focus our attention on microglial phagocytosis that is essential for tissue homeostasis, since it removes apoptotic cells produced by embryonic and postnatal neurogenesis and under pathological conditions. Thus, an increase of neuronal damage and pro-inflammatory profile classicaly described in NPCD could result from an undetected phagocytosis impairment mediated by microglia and non professional phagocytes, such as astrocytes. Supporting these hypothesis, we have observed a number of morphological and molecular anomalies of microglial cells, associated to key phagocytic pahtway of chemoattraction/cell recognition and engulfment of apoptotic cells, such as Purinergic receptors, Cx3cl1/Cx3cr1 pathway, CR3 and Trem2 markers for microglia and Abca1 and Megf10/Merkt signaling for astrocytes in Npc1 compared to age-matched wild-type mice. Evidence acquired within the framework of these studies will be presented and discussed.