Naslov
Niemann-Pick type C disease – a model to study the role of cholesterol in the pathogenesis of Alzheimer's disease

Autori
Katušić Hećimović, Silva ; Malnar, Martina ; Košiček, Marko

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, neobjavljeni rad, znanstveni

Skup
The 19th European Study Group on Lysosomal Diseases (ESGLD

Mjesto i datum
Graz, Austrija, 26.09.2013. - 29.09.2013

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Alzheimer's disease; amyloid-beta; NPC1

Sažetak
Altered metabolism of the amyloid precursor protein (APP) leading to increased generation/accumulation of the amyloid-beta peptide (Abeta) is considered to be a central event in the pathogenesis of Alzheimer’s disease (AD). Recent evidence increasingly implicates that APP metabolism can be modulated by cholesterol levels suggesting that altered cholesterol homeostasis may trigger the pathogenic processes leading to AD. However, the molecular details of the role of cholesterol in the pathogenesis of AD have been largely unknown. The link between altered cholesterol metabolism and AD has been recently revealed in a rare inherited lysosomal storage disorder Niemann-Pick type-C (NPC). Interestingly, NPC disease shares several similarities with AD including neurodegeneration, endosomes-lysosome dysfunction and increased levels of APP-C-terminal fragments (APP-CTFs) and Abeta1, 2, 3. Additionally, studies on AD-animal models revealed that NPC1-dysfunction enhances the progression of AD by increasing Abeta accumulation. More recently, altered expression of NPC1 mRNA/protein were reported in AD patients brains indicating a bidirectional link between NPC1 (dys)function and Alzheimer’s disease. The NPC disease may thus present an innovative model to study the molecular mechanism(s) of cholesterol-mediated APP-CTFs/Abeta accumulation/aggregation in which a defect in a single gene involved in cholesterol trafficking (NPC1) causes AD-like phenotype. In our recent results, we provide evidence for an indirect mechanism of cholesterol-effect upon NPC1-loss-of-function on APP processing. Using NPC1-null cells we demonstrated that increased Abeta in NPC disease is mediated by cholesterol-dependent increased processing of APP by beta-secretase (BACE1)4 probably due to decreased expression of APP at the cell surface and its increased partitioning into cholesterol-rich membranes - lipid rafts5. Furthermore, we showed that cholesterol accumulation in NPC1-null cells sequesters APP and BACE1 in the same enlarged endocytic compartments and that APP and BACE1misstrafficking is dependent on cholesterol levels6. Our findings support that altered endocytic trafficking of APP and BACE1 may be the primary defect in AD and that increased cholesterol levels, such as in NPC disease and sporadic AD, may be the upstream effector that drives these events. References: 1. Yamazaki T, Chang TY, Haass C, Ihara Y. J Biol Chem. 2001 ; 276: 4454-60. 2. Burns M, Gaynor K, Olm V, Mercken M, LaFrancois J, Wang L, Mathews PM, Noble W, Matsuoka Y, Duff K. J Neurosci. 2003 ; 23: 5645-9. 3. Jin LW, Shie FS, Maezawa I, Vincent I, Bird T. Am J Pathol. 2004 ; 164: 975-85. 4. Malnar M, Kosicek M, Mitterreiter S, Omerbasic D, Lichtenthaler SF, Goate A, Hecimovic S. Biochim Biophys Acta. 2010 ; 1802: 682-91. 5. Kosicek M, Malnar M, Goate A, Hecimovic S. Biochem Biophys Res Commun. 2010 ; 393:404-9. 6. Malnar M, Kosicek M, Lisica A, Posavec M, Krolo A, Njavro J, Omerbasic D, Tahirovic S, Hecimovic S. Biochim Biophys Acta. 2012 ; 1822: 1270-83.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti

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