Ossified blood vessels in primary familial brain calcification elicit a neurotoxic astrocyte response

• Published in: Brain (London, England : 1878) England : 1878), 2019-04, Vol.142 (4), p.885-902
• Main Authors: Zarb, Yvette, Weber-Stadlbauer, Ulrike, Kirschenbaum, Daniel, Kindler, Diana Rita, Richetto, Juliet, Keller, Daniel, Rademakers, Rosa, Dickson, Dennis W, Pasch, Andreas, Byzova, Tatiana, Nahar, Khayrun, Voigt, Fabian F, Helmchen, Fritjof, Boss, Andreas, Aguzzi, Adriano, Klohs, Jan, Keller, Annika
• Format: Article
• Language: English
• Subjects: Aged; Animals; Astrocytes - metabolism; Brain - pathology; Brain Diseases - genetics; Calcinosis - pathology; Editor's Choice; Female; Humans; Male; Mice; Mutation; neurotoxic astrocyte; Original; ossification; Ossification, Heterotopic - pathology; Osteogenesis - physiology; Oxidative Stress; PDGFB; Pedigree; prepulse inhibition; primary familial brain calcification; Proto-Oncogene Proteins c-sis - genetics; Proto-Oncogene Proteins c-sis - metabolism; Proto-Oncogene Proteins c-sis - physiology; Receptor, Platelet-Derived Growth Factor beta - genetics; Sodium-Phosphate Cotransporter Proteins, Type III - genetics
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awz032

Brain calcifications are common in aged individuals, but the mechanisms underlying their formation are unclear. Zarb et al. show that in primary familial brain calcification, a neuropsychiatric disorder featuring bilateral vessel-associated calcifications in the basal ganglia, vessel calcification is accompanied by an osteogenic environment which elicits a neurotoxic astrocyte response. Abstract 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 (Pdgfbret/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 Pdgfbret/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 Pdgfbret/ret animals, as assessed by ex vivo and in vivo quantification of calcifications. We also report that serum of Pdgfbret/ret animals does not differ in calcification propensity from control animals and that vessel calcification occurs only in the brains of Pdgfbret/ret animals. Notably, ossification of vessels and astrocytic neurotoxic response