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Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response
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.ORCID iD: 0000-0001-5107-0701
Zurich Univ, Univ Zurich Vetsuisse, Inst Vet Pharmacol & Toxicol, Zurich, Switzerland.ORCID iD: 0000-0002-5278-9993
Zurich Univ, Zurich Univ Hosp, Inst Neuropathol, Zurich, Switzerland.
ETH, Dept Biomed Engn, Zurich, Switzerland;Univ Zurich, Zurich, Switzerland.
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2019 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 142, no 4, p. 885-902Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS , 2019. Vol. 142, no 4, p. 885-902
Keywords [en]
neurotoxic astrocyte, ossification, PDGFB, prepulse inhibition, primary familial brain calcification
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-390284DOI: 10.1093/brain/awz032ISI: 000472805000011PubMedID: 30805583OAI: oai:DiVA.org:uu-390284DiVA, id: diva2:1349699
Available from: 2019-09-09 Created: 2019-09-09 Last updated: 2019-09-09Bibliographically approved

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