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Ossified blood vess...
Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response
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- Zarb, Yvette (author)
- Zurich Univ, Zurich Univ Hosp, Clin Neurosci Ctr, Dept Neurosurg, Zurich, Switzerland;Univ Zurich, Neurosci Ctr Zurich ZNZ, Zurich, Switzerland;Swiss Fed Inst Technol, Zurich, Switzerland
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- Weber-Stadlbauer, Ulrike (author)
- Zurich Univ, Univ Zurich Vetsuisse, Inst Vet Pharmacol & Toxicol, Zurich, Switzerland
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- Kirschenbaum, Daniel (author)
- Zurich Univ, Zurich Univ Hosp, Inst Neuropathol, Zurich, Switzerland
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- Kindler, Diana Rita (author)
- ETH, Dept Biomed Engn, Zurich, Switzerland;Univ Zurich, Zurich, Switzerland
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- Richetto, Juliet (author)
- Zurich Univ, Univ Zurich Vetsuisse, Inst Vet Pharmacol & Toxicol, Zurich, Switzerland
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- Keller, Daniel (author)
- Zurich Univ, Zurich Univ Hosp, Inst Diagnost & Intervent Radiol, Zurich, Switzerland
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Rademakers, Rosa (author)
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- Dickson, Dennis W. (author)
- Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA
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- Pasch, Andreas (author)
- Calciscon AG, Nidau Biel, Switzerland
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- Byzova, Tatiana (author)
- Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH 44106 USA
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- Nahar, Khayrun (author)
- Uppsala universitet,Vaskulärbiologi
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- Voigt, Fabian F. (author)
- Univ Zurich, Neurosci Ctr Zurich ZNZ, Zurich, Switzerland;Swiss Fed Inst Technol, Zurich, Switzerland;Zurich Univ, Brain Res Inst, Zurich, Switzerland
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- Helmchen, Fritjof (author)
- Univ Zurich, Neurosci Ctr Zurich ZNZ, Zurich, Switzerland;Swiss Fed Inst Technol, Zurich, Switzerland;Zurich Univ, Brain Res Inst, Zurich, Switzerland
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- Boss, Andreas (author)
- Zurich Univ, Zurich Univ Hosp, Inst Diagnost & Intervent Radiol, Zurich, Switzerland
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- Aguzzi, Adriano (author)
- Zurich Univ, Zurich Univ Hosp, Inst Neuropathol, Zurich, Switzerland
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- Klohs, Jan (author)
- ETH, Dept Biomed Engn, Zurich, Switzerland;Univ Zurich, Zurich, Switzerland
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- Keller, Annika (author)
- Zurich Univ, Zurich Univ Hosp, Clin Neurosci Ctr, Dept Neurosurg, Zurich, Switzerland;Univ Zurich, Neurosci Ctr Zurich ZNZ, Zurich, Switzerland;Swiss Fed Inst Technol, Zurich, Switzerland
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(creator_code:org_t)
- 2019-02-25
- 2019
- English.
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In: Brain. - : OXFORD UNIV PRESS. - 0006-8950 .- 1460-2156. ; 142:4, s. 885-902
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Abstract
Subject headings
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- Brain calcifications are commonly detected in aged individuals and accompany numerous brain diseases, but their functional importance is not understood. In cases of primary familial brain calcification, an autosomally inherited neuropsychiatric disorder, the presence of bilateral brain calcifications in the absence of secondary causes of brain calcification is a diagnostic criterion. To date, mutations in five genes including solute carrier 20 member 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), myogenesis regulating glycosidase (MYORG), platelet-derived growth factor B (PDGFB) and platelet-derived growth factor receptor beta (PDGFRB), are considered causal. Previously, we have reported that mutations in PDGFB in humans are associated with primary familial brain calcification, and mice hypomorphic for PDGFB (Pdgfb(ret/ret)) present with brain vessel calcifications in the deep regions of the brain that increase with age, mimicking the pathology observed in human mutation carriers. In this study, we characterize the cellular environment surrounding calcifications in Pdgfb(ret/ret) animals and show that cells around vessel-associated calcifications express markers for osteoblasts, osteoclasts and osteocytes, and that bone matrix proteins are present in vessel-associated calcifications. Additionally, we also demonstrate the osteogenic environment around brain calcifications in genetically confirmed primary familial brain calcification cases. We show that calcifications cause oxidative stress in astrocytes and evoke expression of neurotoxic astrocyte markers. Similar to previously reported human primary familial brain calcification cases, we describe high interindividual variation in calcification load in Pdgfb(ret/ret) animals, as assessed by ex vivo and in vivo quantification of calcifications. We also report that serum of Pdgfb(ret/ret) animals does not differ in calcification propensity from control animals and that vessel calcification occurs only in the brains of Pdgfb(ret/ret) animals. Notably, ossification of vessels and astrocytic neurotoxic response is associated with specific behavioural and cognitive alterations, some of which are associated with primary familial brain calcification in a subset of patients.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- neurotoxic astrocyte
- ossification
- PDGFB
- prepulse inhibition
- primary familial brain calcification
Publication and Content Type
- ref (subject category)
- art (subject category)
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Brain
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Zarb, Yvette
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Weber-Stadlbauer ...
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Kirschenbaum, Da ...
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Kindler, Diana R ...
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Richetto, Juliet
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Keller, Daniel
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Rademakers, Rosa
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Dickson, Dennis ...
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Pasch, Andreas
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Byzova, Tatiana
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Nahar, Khayrun
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Voigt, Fabian F.
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Helmchen, Fritjo ...
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Boss, Andreas
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Aguzzi, Adriano
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Klohs, Jan
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Keller, Annika
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- MEDICAL AND HEALTH SCIENCES
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Brain
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Uppsala University