title: Amyloid-β metabolism in Niemann-Pick C disease models and patients.
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.
authors.affiliation: Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy, University of Gothenburg, Mölndal, Gothenburg, Sweden. niklas.mattsson@neuro.gu.se
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.forename: Maria
authors.initials: M
authors.lastname: Olsson
authors.forename: Mikael K
authors.initials: MK
authors.lastname: Gustavsson
authors.forename: Marko
authors.initials: M
authors.lastname: Kosicek
authors.forename: Martina
authors.initials: M
authors.lastname: Malnar
authors.forename: Jan-Eric
authors.initials: JE
authors.lastname: Månsson
authors.forename: Maria
authors.initials: M
authors.lastname: Blomqvist
authors.forename: Johan
authors.initials: J
authors.lastname: Gobom
authors.forename: Ulf
authors.initials: U
authors.lastname: Andreasson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Brinkmalm
authors.forename: Charles
authors.initials: C
authors.lastname: Vite
authors.forename: Silva
authors.initials: S
authors.lastname: Hecimovic
authors.forename: Caroline
authors.initials: C
authors.lastname: Hastings
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002415:Cats; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053719:Tandem Mass Spectrometry; D047392:beta-Cyclodextrins / Q000627:therapeutic use; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D047392:beta-Cyclodextrins; D016875:tau Proteins; D000073738:2-Hydroxypropyl-beta-cyclodextrin