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Amyloid-β metabolis...
Amyloid-β metabolism in Niemann-Pick C disease models and patients.
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- Mattsson, Niklas, 1979 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Olsson, Maria, 1959 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för klinisk kemi och transfusionsmedicin,Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
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- Gustavsson, Mikael K (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biologi och miljövetenskap,Department of Biological and Environmental Sciences
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Kosicek, Marko (author)
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Malnar, Martina (author)
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- Månsson, Jan-Eric, 1946 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology
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- Blomqvist, Maria K., 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology
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- Gobom, Johan (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Andreasson, Ulf, 1968 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Brinkmalm, Gunnar (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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Vite, Charles (author)
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Hecimovic, Silva (author)
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Hastings, Caroline (author)
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- Blennow, Kaj, 1958 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Zetterberg, Henrik, 1973 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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- Portelius, Erik, 1977 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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(creator_code:org_t)
- 2012-09-01
- 2012
- English.
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In: Metabolic brain disease. - : Springer Science and Business Media LLC. - 1573-7365 .- 0885-7490. ; 27:4, s. 573-85
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- Amyloid beta-Peptides
- analysis
- cerebrospinal fluid
- metabolism
- Amyloid beta-Protein Precursor
- metabolism
- Animals
- Carrier Proteins
- genetics
- Cats
- Cell Line
- Tumor
- Child
- Child
- Preschool
- Chromatography
- High Pressure Liquid
- Female
- Humans
- Immunoprecipitation
- Infant
- Male
- Membrane Glycoproteins
- genetics
- Mutation
- Missense
- genetics
- Niemann-Pick Disease
- Type C
- genetics
- metabolism
- Spectrometry
- Mass
- Matrix-Assisted Laser Desorption-Ionization
- Tandem Mass Spectrometry
- beta-Cyclodextrins
- therapeutic use
- tau Proteins
- metabolism
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Mattsson, Niklas ...
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Olsson, Maria, 1 ...
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Gustavsson, Mika ...
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Kosicek, Marko
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Malnar, Martina
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Månsson, Jan-Eri ...
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Blomqvist, Maria ...
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Gobom, Johan
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Andreasson, Ulf, ...
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Brinkmalm, Gunna ...
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Vite, Charles
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Hecimovic, Silva
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Hastings, Caroli ...
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Blennow, Kaj, 19 ...
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Zetterberg, Henr ...
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Portelius, Erik, ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Metabolic brain ...
- By the university
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University of Gothenburg