Niemann Pathogenesis

Pacheco CD, Lieberman AP (2008) The pathogenesis of Niemann-Pick type C disease a role for autophagy Expert Rev Mol Med 10 e26... 

Other lines of evidence also support the notion that deregulated cholesterol homeostasis may contribute to the AD pathogenesis. AD patients have been reported to develop intracellular A/1 accumulation in the late endo-somes and lysosomes. Similar pathological features, including swollen late endosomes and A/ accumulation, have also been reported in Niemann-Pick type C disease patients [52,53], Npcl deficient mice as well as in mouse models of AD [54,55]. The Npcl gene product is essential for the mobihzation of cellular cholesterol. Excess cholesterol can be transported into endoplasmic reticulum and esterified by acyl co enzyme A cholesterol acyltransferase (ACAT) and stored in lipid droplets. Inhibition of ACAT activity has been reported to reduce A/3 levels in vitro and plaque pathology in animal models of AD [56,57]. 

Schuchman EH (2007) The pathogenesis and treatment of acid sphingomyeUnase-deficient Niemann—Pick disease. J Inherit Metab Dis 30 654-663... 

Schuchman, E. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inher Metabol Dis 30 (2007) 654-663. 

Although our present knowledge of the chemistry and metabolism of sphingomyelin has not provided an answer to the pathogenesis of Niemann-Pick disease, the known facts will briefly be summarized with the hope that they will prepare the reader for further developments in the field of lipoidoses. 

Our knowledge of the fate of sphingomyelin in cells is still so fragmentary that all explanations for the pathogenesis of Niemann-Pick disease can only be hypothetical. 

Partial answers to the pathogenesis of Niemann-Pick disease have been obtained recently. An enzyme, sphingomyelinase, which hydrolyzes sphingomyelin to yield phosphorylcholine and ceramide has been found and partially purified from liver. Drastic reduction in the activity of this enzyme has been found in at least some patients with Niemann-Pick disease (see Fig. 3-40). In other cases the biochemical defect remains unknown [125], especially in those forms of the disease in which cholesterol accumulates (Nova Scotia variant). 

Sphingosine + CDP-choline Fig. 3-40. Pathogenesis of Niemann-Pick disease... 

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