Gadolinium based contrast agents (GBCAs) are widely used in clinical MRI since the mid-1980s. Recently, concerns have been raised that trace amounts of Gadolinium (Gd), detected in brains even long time after GBCA application, may cause yet unrecognized clinical consequences. We therefore assessed the behavioral phenotype, neuro-histopathology, and Gd localization after repeated administration of linear (gadodiamide) or macrocyclic (gadobutrol) GBCA in rats. While most behavioral tests revealed no difference between treatment groups, we observed a transient and reversible decrease of the startle reflex after gadodiamide application. Residual Gd in the lateral cerebellar nucleus was neither associated with a general gene expression pathway deregulation nor with neuronal cell loss, but in gadodiamide-treated rats Gd was associated with the perineuronal net protein aggrecan and segregated to high molecular weight fractions. Our behavioral finding together with Gd distribution and speciation support a substance class difference for Gd presence in the brain after GBCA application.

Pathogenic variants of the huntingtin (HTT) protein and their aggregation have been investigated in great detail in brains of Huntington's disease patients and HTT-transgenic animals. However, little is known about the physiological brain region-and cell type-specific HTT expression pattern in wild type mice and a potential recruitment of endogenous HTT to other pathogenic protein aggregates such as amyloid plaques in cross seeding events. Employing a monoclonal anti-HTT antibody directed against the HTT mid-region and using brain tissue of three different mouse strains, we detected prominent immunoreactivity in a number of brain areas, particularly in cholinergic cranial nerve nuclei, while ubiquitous neuronal staining appeared faint. The region-specific distribution of endogenous HTT was found to be comparable in wild type rat and hamster brain. In human amyloid precursor protein transgenic Tg2576 mice with amyloid plaque pathology, similar neuronal HTT expression patterns and a distinct association of HTT with Abeta plaques were revealed by immunohistochemical double labelling. Additionally, the localization of HTT in reactive astrocytes was demonstrated for the first time in a transgenic Alzheimer's disease animal model. Both, plaque association of HTT and occurrence in astrocytes appeared to be age-dependent. Astrocytic HTT gene and protein expression was confirmed in primary cultures by RT-qPCR and by immunocytochemistry. We provide the first detailed analysis of physiological HTT expression in rodent brain and, under pathological conditions, demonstrate HTT aggregation in proximity to Abeta plaques and Abeta-induced astrocytic expression of endogenous HTT in Tg2576 mice.

Background: The intracellular ion channel type 1 inositol 1,4,5-trisphosphate receptor (IP 3 R1) releases Ca 2+ from the endoplasmic reticulum upon stimulation with IP 3 . Perturbation of IP 3 R1 has been implicated in the development of several neurodegenerative disorders, including Huntington disease (HD). Objective: To elucidate the putative role of IP 3 R1 phosphorylation in HD, we investigated IP 3 R1 levels and protein phosphorylation state in the striatum, hippocampus and cerebellum of four murine HD models. Methods: Quantitative immunoblotting with antibodies to IP 3 R1 protein and its phosphorylated serines 1589 and 1755 was applied to brain homogenates from R6/1 mice to study early-onset aggressive HD. To determine if IP 3 R1 changes precede overt pathology, we immunostained tissues from the regions of interest and several control regions for IP 3 R1 in tgHD CAG51n rats and BACHD and zQ175DNKI mice, all recognized models for late-onset HD. Results: R6/1 mice had reduced total IP 3 R1 immunoreactivity, variably reduced serine1755-phosphorylation in all regions investigated, and reduced serine1589-phosphorylation in cerebellum. IP 3 R1 levels were decreased relative to cell-specific marker proteins. In tgHD CAG51n rats we found reduced IP 3 R1 levels in the cerebellum, but otherwise unchanged IP 3 R1 phosphorylation and protein levels. In BACHD and zQ175DNKI mice only age-dependent decline of IP 3 R1 was observed. Conclusion:The level and phosphorylation of IP 3 R1 is reduced to a variable degree in the different HD models relative to control, indicating that earlier findings in more aggressive exon 1-truncated HD models may not be replicated in models with higher construct validity. Further analysis of possible coupling of reduced IP 3 R1 levels with development of neuropathological responses and cell-specific degeneration is warranted.

No abstract