TY - JOUR
T1 - Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response
AU - Zarb, Yvette
AU - Weber-Stadlbauer, Ulrike
AU - Kirschenbaum, Daniel
AU - Kindler, Diana Rita
AU - Richetto, Juliet
AU - Keller, Daniel
AU - Rademakers, Rosa
AU - Dickson, Dennis W.
AU - Pasch, Andreas
AU - Byzova, Tatiana
AU - Nahar, Khayrun
AU - Voigt, Fabian F.
AU - Helmchen, Fritjof
AU - Boss, Andreas
AU - Aguzzi, Adriano
AU - Klohs, Jan
AU - Keller, Annika
N1 - Publisher Copyright:
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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 β (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.
AB - 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 β (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.
KW - PDGFB
KW - neurotoxic astrocyte
KW - ossification
KW - prepulse inhibition
KW - primary familial brain calcification
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UR - http://www.scopus.com/inward/citedby.url?scp=85064239142&partnerID=8YFLogxK
U2 - 10.1093/brain/awz032
DO - 10.1093/brain/awz032
M3 - Article
C2 - 30805583
AN - SCOPUS:85064239142
SN - 0006-8950
VL - 142
SP - 885
EP - 902
JO - Brain
JF - Brain
IS - 4
ER -