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01.12.2012 | Original Paper

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

verfasst von: Niklas Mattsson, Maria Olsson, Mikael K. Gustavsson, Marko Kosicek, Martina Malnar, Jan-Eric Månsson, Maria Blomqvist, Johan Gobom, Ulf Andreasson, Gunnar Brinkmalm, Charles Vite, Silva Hecimovic, Caroline Hastings, Kaj Blennow, Henrik Zetterberg, Erik Portelius

Erschienen in: Metabolic Brain Disease | Ausgabe 4/2012

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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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Titel: Amyloid-β metabolism in Niemann-Pick C disease models and patients
verfasst von: Niklas Mattsson
Maria Olsson
Mikael K. Gustavsson
Marko Kosicek
Martina Malnar
Jan-Eric Månsson
Maria Blomqvist
Johan Gobom
Ulf Andreasson
Gunnar Brinkmalm
Charles Vite
Silva Hecimovic
Caroline Hastings
Kaj Blennow
Henrik Zetterberg
Erik Portelius
Publikationsdatum: 01.12.2012
Verlag: Springer US
Erschienen in: Metabolic Brain Disease / Ausgabe 4/2012
Print ISSN: 0885-7490
Elektronische ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-012-9332-8

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

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