Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1 ^−/− mouse

Abstract

Niemann-Pick type C disease is largely attributable to an inactivating mutation of NPC1 protein, which normally aids movement of unesterified cholesterol (C) from the endosomal/lysosomal (E/L) compartment to the cytosolic compartment of cells throughout the body. This defect results in activation of macrophages in many tissues, progressive liver disease, and neurodegeneration. In the npc1 ؊/؊ mouse, a model of this disease, the whole-animal C pool expands from 2,082 to 4,925 mg/kg body weight (bw) and the hepatic C pool increases from 132 to 1,485 mg/kg bw between birth and 49 days of age. A single dose of 2-hydroxypropyl-␤-cyclodextrin (CYCLO) administered at 7 days of age immediately caused this sequestered C to flow from the lysosomes to the cytosolic pool in many organs, resulting in a marked increase in cholesteryl esters, suppression of C but not fatty acid synthesis, down-regulation of genes controlled by sterol regulatory element 2, and up-regulation of many liver X receptor target genes. There was also decreased expression of proinflammatory proteins in the liver and brain. In the liver, where the rate of C sequestration equaled 79 mg⅐d ؊1 ⅐kg ؊1 , treatment with CYCLO within 24 h increased C movement out of the E/L compartment from near 0 to 233 mg⅐d ؊1 ⅐kg ؊1 . By 49 days of age, this single injection of CYCLO resulted in a reduction in whole-body C burden of >900 mg/kg, marked improvement in liver function tests, much less neurodegeneration, and, ultimately, significant prolongation of life. These findings suggest that CYCLO acutely reverses the lysosomal transport defect seen in NPC disease.cholesterol ͉ lysosome ͉ cyclodextrin ͉ liver X receptor

Relative efficacy of nicotinamide treatment of a mouse model of infantile Niemann-Pick C1 disease

“…The extensions of survival fall in the class of what tamoxifen and vitamin E accomplished (expressed in failures of weight gain which translates into about a 3-fold greater survival; Bascunan-Castillo, et al, 2004) and are significantly better than curcumin's effect (barely significant in our hands; Borbon, et al, 2012). However, it is far less than what treatment with hydroxypropyl-beta-cyclodextrin, especially when delivered intrathecally, accomplishes (Liu, et al, 2009).…”

“…There has been an extensive search for drugs to treat the disorder and one, hydroxypropyl-beta-cyclodextrin (HPBCD; Camargo, et al, 2001;Liu, et al, 2009) is currently in phase II trials. However, to date, this treatment only slows the disorder and other treatment modalities are needed.…”

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

“…4D). In mouse brains, CE contents are reported to be very low (32). We attempted to measure CE in A1+ mouse brains by separating the CE fraction from the free cholesterol fraction using column chromatography Full-length m+hAPP is detected by using antiserum 369, which recognizes both mouse and human APP (n = 7).…”

Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells

“…Clinical manifestations of NPC disease include neuronal degeneration, hepatosplenomegaly, and effects in other organs (1). No effective treatment is currently available for NPC disease (7), but recent studies involving administration of hydroxypropyl-β-cyclodextrin (HPβCD) in npc1 −/− mice showed improvements in viability, hepatopathology, and neuropathology, including clearance of cholesterol and glycosphingolipids (8)(9)(10)(11)(12). These animal studies were not designed to address the molecular and cellular mechanisms by which cyclodextrins (CDs) could reduce the cholesterol accumulation in LSOs.…”