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Amyloid-β metabolism in Niemann-Pick C disease models and patients

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Abstract

Niemann-Pick type C (NPC) is a progressive neurodegenerative lysosomal disease with altered cellular lipid trafficking. The metabolism of amyloid-β (Aβ) - previously mainly studied in Alzheimer’s disease - has been suggested to be altered in NPC. Here we aimed to perform a detailed characterization of metabolic products from the amyloid precursor protein (APP) in NPC models and patients. We used multiple analytical technologies, including immunoassays and immunoprecipitation followed by mass spectrometry (IP-MS) to characterize Aβ peptides and soluble APP fragments (sAPP-α/β) in cell media from pharmacologically (U18666A) and genetically (NPC1 −/− ) induced NPC cell models, and cerebrospinal fluid (CSF) from NPC cats and human patients. The pattern of Aβ peptides and sAPP-α/β fragments in cell media was differently affected by NPC-phenotype induced by U18666A treatment and by NPC1 −/− genotype. U18666A treatment increased the secreted media levels of sAPP-α, AβX-40 and AβX-42 and reduced the levels of sAPP-β, Aβ1-40 and Aβ1-42, while IP-MS showed increased relative levels of Aβ5-38 and Aβ5-40 in response to treatment. NPC1 −/− cells had reduced media levels of sAPP-α and Aβ1-16, and increased levels of sAPP-β. NPC cats had altered CSF distribution of Aβ peptides compared with normal cats. Cats treated with the potential disease-modifying compound 2-hydroxypropyl-β-cyclodextrin had increased relative levels of short Aβ peptides including Aβ1-16 compared with untreated cats. NPC patients receiving β-cyclodextrin had reduced levels over time of CSF Aβ1-42, AβX-38, AβX-40, AβX-42 and sAPP-β, as well as reduced levels of the axonal damage markers tau and phosphorylated tau. We conclude that NPC models have altered Aβ metabolism, but with differences across experimental systems, suggesting that NPC1-loss of function, such as in NPC1 −/− cells, or NPC1-dysfunction, seen in NPC patients and cats as well as in U18666A-treated cells, may cause subtle but different effects on APP degradation pathways. The preliminary findings from NPC cats suggest that treatment with cyclodextrin may have an impact on APP processing pathways. CSF Aβ, sAPP and tau biomarkers were dynamically altered over time in human NPC patients.

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References

  • Auer IA, Schmidt ML, Lee VM, Curry B, Suzuki K, Shin RW, Pentchev PG, Carstea ED, Trojanowski JQ (1995) Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer’s disease. Acta Neuropathol 90(6):547–551

    Article  PubMed  CAS  Google Scholar 

  • Biedler JL, Roffler-Tarlov S, Schachner M, Freedman LS (1978) Multiple neurotransmitter synthesis by human neuroblastoma cell lines and clones. Cancer Res 38(11 Pt 1):3751–3757

    PubMed  CAS  Google Scholar 

  • Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6(3):131–144

    Article  PubMed  CAS  Google Scholar 

  • Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R, Grundman M, Liu E, for the AABI (2012) Effect of immunotherapy with Bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol 69(8):1002–1010

    Google Scholar 

  • Bodovitz S, Klein WL (1996) Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem 271(8):4436–4440

    Article  PubMed  CAS  Google Scholar 

  • Boland B, Smith DA, Mooney D, Jung SS, Walsh DM, Platt FM (2010) Macroautophagy is not directly involved in the metabolism of amyloid precursor protein. J Biol Chem 285(48):37415–37426

    Google Scholar 

  • Borbon IA, Erickson RP (2011) Interactions of Npc1 and amyloid accumulation/deposition in the APP/PS1 mouse model of Alzheimer’s. J Appl Genet 52(2):213–218

    Article  PubMed  CAS  Google Scholar 

  • Brinkmalm G, Portelius E, Ohrfelt A, Mattsson N, Persson R, Gustavsson MK, Vite CH, Gobom J, Mansson JE, Nilsson J, Halim A, Larson G, Ruetschi U, Zetterberg H, Blennow K, Brinkmalm A (2012) An online nano-LC-ESI-FTICR-MS method for comprehensive characterization of endogenous fragments from amyloid beta and amyloid precursor protein in human and cat cerebrospinal fluid. J Mass Spectrom 47(5):591–603

    Article  PubMed  CAS  Google Scholar 

  • Burns M, Gaynor K, Olm V, Mercken M, LaFrancois J, Wang L, Mathews PM, Noble W, Matsuoka Y, Duff K (2003) Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo. J Neurosci 23(13):5645–5649

    PubMed  CAS  Google Scholar 

  • Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 58(1):42–51

    Article  PubMed  CAS  Google Scholar 

  • Crestini A, Napolitano M, Piscopo P, Confaloni A, Bravo E (2006) Changes in cholesterol metabolism are associated with PS1 and PS2 gene regulation in SK-N-BE. J Mol Neurosci 30(3):311–322

    Article  PubMed  CAS  Google Scholar 

  • Davis W Jr (2008) The cholesterol transport inhibitor U18666a regulates amyloid precursor protein metabolism and trafficking in N2aAPP “Swedish” cells. Curr Alzheimer Res 5(5):448–456

    Article  PubMed  CAS  Google Scholar 

  • Erickson RP, Larson-Thome K, Weberg L, Szybinska A, Mossakowska M, Styczynska M, Barcikowska M, Kuznicki J (2008) Variation in NPC1, the gene encoding Niemann-Pick C1, a protein involved in intracellular cholesterol transport, is associated with Alzheimer disease and/or aging in the Polish population. Neurosci Lett 447(2–3):153–157

    Article  PubMed  CAS  Google Scholar 

  • Grimm MO, Grimm HS, Hartmann T (2007) Amyloid beta as a regulator of lipid homeostasis. Trends Mol Med 13(8):337–344

    Article  PubMed  CAS  Google Scholar 

  • Hansson O, Zetterberg H, Vanmechelen E, Vanderstichele H, Andreasson U, Londos E, Wallin A, Minthon L, Blennow K (2010) Evaluation of plasma Abeta(40) and Abeta(42) as predictors of conversion to Alzheimer’s disease in patients with mild cognitive impairment. Neurobiol Aging 31(3):357–367

    Article  PubMed  CAS  Google Scholar 

  • Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185

    Article  PubMed  CAS  Google Scholar 

  • Hecimovic S, Wang J, Dolios G, Martinez M, Wang R, Goate AM (2004) Mutations in APP have independent effects on Abeta and CTFgamma generation. Neurobiol Dis 17(2):205–218

    Article  PubMed  CAS  Google Scholar 

  • Holmes O, Paturi S, Ye W, Wolfe MS, Selkoe DJ (2012) Effects of membrane lipids on the activity and processivity of purified gamma-secretase. Biochemistry 51(17):3565–3575

    Article  PubMed  CAS  Google Scholar 

  • Hook V, Toneff T, Bogyo M, Greenbaum D, Medzihradszky KF, Neveu J, Lane W, Hook G, Reisine T (2005) Inhibition of cathepsin B reduces beta-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate beta-secretase of Alzheimer’s disease. Biol Chem 386(9):931–940

    Article  PubMed  CAS  Google Scholar 

  • Jin LW, Shie FS, Maezawa I, Vincent I, Bird T (2004) Intracellular accumulation of amyloidogenic fragments of amyloid-beta precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities. Am J Pathol 164(3):975–985

    Article  PubMed  CAS  Google Scholar 

  • Kagedal K, Kim WS, Appelqvist H, Chan S, Cheng D, Agholme L, Barnham K, McCann H, Halliday G, Garner B (2010) Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimer’s disease. Biochim Biophys Acta 1801(8):831–838

    Article  PubMed  CAS  Google Scholar 

  • Kodam A, Maulik M, Peake K, Amritraj A, Vetrivel KS, Thinakaran G, Vance JE, Kar S (2010) Altered levels and distribution of amyloid precursor protein and its processing enzymes in Niemann-Pick type C1-deficient mouse brains. Glia 58(11):1267–1281

    Article  PubMed  CAS  Google Scholar 

  • Koh CH, Whiteman M, Li QX, Halliwell B, Jenner AM, Wong BS, Laughton KM, Wenk M, Masters CL, Beart PM, Bernard O, Cheung NS (2006) Chronic exposure to U18666A is associated with oxidative stress in cultured murine cortical neurons. J Neurochem 98(4):1278–1289

    Article  PubMed  CAS  Google Scholar 

  • Kosicek M, Malnar M, Goate A, Hecimovic S (2010) Cholesterol accumulation in Niemann Pick type C (NPC) model cells causes a shift in APP localization to lipid rafts. Biochem Biophys Res Commun 393(3):404–409

    Article  PubMed  CAS  Google Scholar 

  • Lange Y, Ye J, Rigney M, Steck T (2000) Cholesterol movement in Niemann-Pick type C cells and in cells treated with amphiphiles. J Biol Chem 275(23):17468–17475

    Article  PubMed  CAS  Google Scholar 

  • Malnar M, Kosicek M, Mitterreiter S, Omerbasic D, Lichtenthaler SF, Goate A, Hecimovic S (2010) Niemann-Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface and its increased processing through the beta-secretase pathway. Biochim Biophys Acta 1802(7–8):682–691

    PubMed  CAS  Google Scholar 

  • Mattsson N, Zetterberg H, Bianconi S, Yanjanin NM, Fu R, Mansson JE, Porter FD, Blennow K (2011) Gamma-secretase-dependent amyloid-beta is increased in Niemann-Pick type C: a cross-sectional study. Neurology 76(4):366–372

    Article  PubMed  CAS  Google Scholar 

  • Mattsson N, Zetterberg H, Bianconi S, Yanjanin NM, Fu R, Mansson JE, Porter FD, Blennow K (2012) Miglustat treatment may reduce cerebrospinal fluid levels of the axonal degeneration marker tau in Niemann-Pick type C. JIMD Reports 3:45–52. doi:10.1007/8904_2011_47

    Google Scholar 

  • Mattsson N, Portelius E, Rolstad S, Gustavsson M, Andreasson U, Stridsberg M, Wallin A, Blennow K, Zetterberg H (2012a) Longitudinal cerebrospinal fluid biomarkers over four years in mild cognitive impairment. J Alzheimers Dis 30(4):767–778

    PubMed  CAS  Google Scholar 

  • Mattsson N, Rajendran L, Zetterberg H, Gustavsson M, Andreasson U, Olsson M, Brinkmalm G, Lundkvist J, Jacobson LH, Perrot L, Neumann U, Borghys H, Mercken M, Dhuyvetter D, Jeppsson F, Blennow K, Portelius E (2012b) BACE1 Inhibition induces a specific cerebrospinal fluid beta-amyloid pattern that identifies drug effects in the central nervous system. PLoS One 7(2):e31084

    Article  PubMed  CAS  Google Scholar 

  • Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1(5):345–347

    Article  PubMed  CAS  Google Scholar 

  • Nixon RA, Yang DS, Lee JH (2008) Neurodegenerative lysosomal disorders: a continuum from development to late age. Autophagy 4(5):590–599

    PubMed  CAS  Google Scholar 

  • Olson L, Humpel C (2010) Growth factors and cytokines/chemokines as surrogate biomarkers in cerebrospinal fluid and blood for diagnosing Alzheimer’s disease and mild cognitive impairment. Exp Gerontol 45(1):41–46

    Article  PubMed  CAS  Google Scholar 

  • Olsson A, Vanderstichele H, Andreasen N, De Meyer G, Wallin A, Holmberg B, Rosengren L, Vanmechelen E, Blennow K (2005) Simultaneous measurement of beta-amyloid(1–42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin Chem 51(2):336–345

    Article  PubMed  CAS  Google Scholar 

  • Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE (2007) Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 6(9):765–772

    Article  PubMed  CAS  Google Scholar 

  • Patterson MC, Hendriksz CJ, Walterfang M, Sedel F, Vanier MT, Wijburg F, on behalf of the NPCGWG (2012) Recommendations for the diagnosis and management of Niemann-Pick disease type C: An update. Mol Genet Metab 106(3):330–344

    Google Scholar 

  • Peake KB, Vance JE (2012) Normalization of cholesterol homeostasis by 2-hydroxypropyl-beta-cyclodextrin in neurons and glia from Niemann-Pick C1-deficient mice. J Biol Chem 287(12):9290–9298

    Google Scholar 

  • Pineda M, Wraith JE, Mengel E, Sedel F, Hwu WL, Rohrbach M, Bembi B, Walterfang M, Korenke GC, Marquardt T, Luzy C, Giorgino R, Patterson MC (2009) Miglustat in patients with Niemann-Pick disease Type C (NP-C): a multicenter observational retrospective cohort study. Mol Genet Metab 98(3):243–249

    Article  PubMed  CAS  Google Scholar 

  • Portelius E, Westman-Brinkmalm A, Zetterberg H, Blennow K (2006) Determination of beta-Amyloid Peptide Signatures in Cerebrospinal Fluid Using Immunoprecipitation-Mass Spectrometry. J Proteome Res 5(4):1010–1016

    Article  PubMed  CAS  Google Scholar 

  • Portelius E, Tran AJ, Andreasson U, Persson R, Brinkmalm G, Zetterberg H, Blennow K, Westman-Brinkmalm A (2007) Characterization of amyloid beta peptides in cerebrospinal fluid by an automated immunoprecipitation procedure followed by mass spectrometry. J Proteome Res 6(11):4433–4439

    Article  PubMed  CAS  Google Scholar 

  • Portelius E, Van Broeck B, Andreasson U, Gustavsson MK, Mercken M, Zetterberg H, Borghys H, Blennow K (2010) Acute effect on the Abeta isoform pattern in CSF in response to gamma-secretase modulator and inhibitor treatment in dogs. J Alzheimers Dis 21(3):1005–1012

    PubMed  CAS  Google Scholar 

  • Portelius E, Mattsson N, Andreasson U, Blennow K, Zetterberg H (2011a) Novel abeta isoforms in Alzheimer’s disease - their role in diagnosis and treatment. Curr Pharm Des 17(25):2594–2602

    Article  PubMed  CAS  Google Scholar 

  • Portelius E, Price E, Brinkmalm G, Stiteler M, Olsson M, Persson R, Westman-Brinkmalm A, Zetterberg H, Simon AJ, Blennow K (2011b) A novel pathway for amyloid precursor protein processing. Neurobiol Aging 32(6):1090–1098

    Article  PubMed  CAS  Google Scholar 

  • Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA (2000) Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis 7(4):321–331

    Article  PubMed  CAS  Google Scholar 

  • Roff CF, Goldin E, Comly ME, Cooney A, Brown A, Vanier MT, Miller SP, Brady RO, Pentchev PG (1991) Type C Niemann-Pick disease: use of hydrophobic amines to study defective cholesterol transport. Dev Neurosci 13(4–5):315–319

    Article  PubMed  CAS  Google Scholar 

  • Rosen C, Andreasson U, Mattsson N, Marcusson J, Minthon L, Andreasen N, Blennow K, Zetterberg H (2012) Cerebrospinal fluid profiles of amyloid beta-related biomarkers in Alzheimer’s disease. Neuromolecular Med 14(1):65–73

    Article  PubMed  CAS  Google Scholar 

  • Rosenbaum AI, Maxfield FR (2011) Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches. J Neurochem 116(5):789–795

    Article  PubMed  CAS  Google Scholar 

  • Runz H, Rietdorf J, Tomic I, de Bernard M, Beyreuther K, Pepperkok R, Hartmann T (2002) Inhibition of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci 22(5):1679–1689

    PubMed  CAS  Google Scholar 

  • Saito Y, Suzuki K, Nanba E, Yamamoto T, Ohno K, Murayama S (2002) Niemann-Pick type C disease: accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apolipoprotein E epsilon 4 homozygosity. Ann Neurol 52(3):351–355

    Article  PubMed  CAS  Google Scholar 

  • Selkoe DJ (1991) The molecular pathology of Alzheimer’s disease. Neuron 6(4):487–498

    Article  PubMed  CAS  Google Scholar 

  • Sidera C, Parsons R, Austen B (2005) The regulation of beta-secretase by cholesterol and statins in Alzheimer’s disease. J Neurol Sci 229–230:269–273

    Article  PubMed  Google Scholar 

  • Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95(11):6460–6464

    Article  PubMed  CAS  Google Scholar 

  • Somers KL, Royals MA, Carstea ED, Rafi MA, Wenger DA, Thrall MA (2003) Mutation analysis of feline Niemann-Pick C1 disease. Mol Genet Metab 79(2):99–103

    Article  PubMed  CAS  Google Scholar 

  • Stachel SJ, Coburn CA, Steele TG, Jones KG, Loutzenhiser EF, Gregro AR, Rajapakse HA, Lai MT, Crouthamel MC, Xu M, Tugusheva K, Lineberger JE, Pietrak BL, Espeseth AS, Shi XP, Chen-Dodson E, Holloway MK, Munshi S, Simon AJ, Kuo L, Vacca JP (2004) Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1). J Med Chem 47(26):6447–6450

    Article  PubMed  CAS  Google Scholar 

  • Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68(10):930–941

    Article  PubMed  CAS  Google Scholar 

  • Takeda K, Araki W, Akiyama H, Tabira T (2004) Amino-truncated amyloid beta-peptide (Abeta5-40/42) produced from caspase-cleaved amyloid precursor protein is deposited in Alzheimer’s disease brain. FASEB J 18(14):1755–1757

    PubMed  CAS  Google Scholar 

  • Vite CH, Ding W, Bryan C, O’Donnell P, Cullen K, Aleman D, Haskins ME, Van Winkle T (2008) Clinical, electrophysiological, and serum biochemical measures of progressive neurological and hepatic dysfunction in feline Niemann-Pick type C disease. Pediatr Res 64(5):544–549

    Article  PubMed  CAS  Google Scholar 

  • Ward S, O’Donnell P, Fernandez S, Vite CH (2010) 2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease. Pediatr Res 68(1):52–56

    Article  PubMed  CAS  Google Scholar 

  • Yamazaki T, Chang TY, Haass C, Ihara Y (2001) Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann-pick type C cells. J Biol Chem 276(6):4454–4460

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Åsa Källén, Monica Christiansson, Sara Hullberg and Dzemila Secic for excellent technical assistance. We would also like to thank Chris Hempel for her support of this work. This study was supported by grants from Sahlgrenska University Hospital, Sahlgrenska Academy, the Lundbeck Foundation, Stiftelsen Psykiatriska Forskningsfonden, Stiftelsen Gamla Tjänarinnor, Uppsala Universitets Medicinska Fakultet stiftelse för psykiatrisk och neurologisk forskning, the Swedish Brain Fund, Göteborgs läkaresällskap, Thuréus stiftelse, Pfannenstills stiftelse, Demensfonden, Magn. Bergvalls stiftelse, Gun och Bertil Stohnes stiftelse, Sweden and Ministry of Science, Education and Sports of the Republic of Croatia (098-0982522-2525 to S.H.).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy, University of Gothenburg, Mölndal, Gothenburg, Sweden

    Niklas Mattsson, Maria Olsson, Mikael K. Gustavsson, Jan-Eric Månsson, Maria Blomqvist, Johan Gobom, Ulf Andreasson, Gunnar Brinkmalm, Kaj Blennow, Henrik Zetterberg & Erik Portelius

  2. Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia

    Marko Kosicek, Martina Malnar & Silva Hecimovic

  3. School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Charles Vite

  4. Children’s Hospital & Research Center Oakland, Oakland, CA, USA

    Caroline Hastings

  5. Clinical Neurochemistry Laboratory, V-huset, Sahlgrenska University Hospital/Mölndal, Mölndal, Gothenburg, S-431 20, Sweden

    Niklas Mattsson

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  1. Niklas Mattsson
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Supplementary Fig. 1

Effects of BACE1-inhibition on NPC phenotype cells. SH-SY5Y APP695wt cells were treated with DMSO, BACE1 inhibition with β-secretase inhibitor IV (Calbiochem, Merck), and/or U18666A. Cell media concentrations of Aβ1-40 (A), Aβ1-42 (B), AβX-40 (C) and AβX-42 (D) were determined using fluorescent bead-based assay. Each data point represents individual cell cultures. Treatment with a BACE1 inhibitor reduced Aβ1-40 and Aβ1-42 levels. (JPEG 55 kb)

High resolution image (TIFF 1103 kb)

Supplementary Fig. 2

Effects of cathepsin B-inhibition on NPC phenotype cells. SH-SY5Y APP695wt cells were treated with DMSO, cathepsin B inhibition with Z-FA-FMK (BD Biosciences, San Jose, CA, USA), and/or U18666A. Cell media concentrations of Aβ1-40 (A), Aβ1-42 (B), AβX-40 (C) and AβX-42 (D) were determined using fluorescent bead-based assay. Each data point represents individual cell cultures. Cathepsin B inhibition reduced AβX-40 and AβX-42 levels in U18666A-treated cells almost to the levels as in vehicle (DMSO)-treated cells. (JPEG 57 kb)

High resolution image (TIFF 1098 kb)

Supplementary Fig. 3

Effects of NPC1−/− on release of Aβ peptides. NPC1wt and NPC1−/− CHO cells were transiently transfected with either APPwt or APPsw construct. Cell media concentrations of Aβ1-40, Aβ1-42, AβX-40 and AβX-42 were determined using fluorescent bead-based assay (FORM) and/or electrochemiluminescent based assay (MSD). Each data point represents individual cell cultures. NPC1 −/− genotype did not have a major effect on media levels of Aβ1-40, Aβ1-42, AβX-40 and AβX-42. (JPEG 64 kb)

High resolution image (TIFF 1141 kb)

Supplementary Fig. 4

Release of Aβ peptides from C99 transfected cells. NPC1wt and NPC1−/− CHO cells were transiently transfected with either APPswe or C99 construct. Signals of Aβ1-40, Aβ1-41 and Aβ1-42 were determined in the cell media with IP-MALDI-TOFMS. Each data point represents individual cell cultures. IP-MALDI-TOFMS analysis showed elevated relative Aβ1-41 signals and reduced relative Aβ1-40 and Aβ1-42 signals in C99 transfected cells compared to APPswe transfected cells. NPC1 −/− genotype increased the relative Aβ1-41 signal even more. (JPEG 35 kb)

High resolution image (TIFF 642 kb)

Supplementary Fig. 5

Aβ peptides in cat CSF. Aβ1-16, Aβ6-28, Aβ1-28, Aβ6-40, Aβ1-34, Aβ1-37, Aβ1-38 and Aβ1-39 peptides were determined by IP-MALDI-TOFMS in CSF from control and cyclodextrin treated/untreated NPC1-cats. Each data point represents individual animals. Some of the cats treated with cyclodextrin showed increased relative levels of Aβ1-16, Aβ6-28 and Aβ1-28 compared to the other groups. (JPEG 54 kb)

High resolution image (TIFF 958 kb)

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Mattsson, N., Olsson, M., Gustavsson, M.K. et al. Amyloid-β metabolism in Niemann-Pick C disease models and patients. Metab Brain Dis 27, 573–585 (2012). https://doi.org/10.1007/s11011-012-9332-8

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