Olfactory cell cultures to investigate health effects of air pollution exposure: Implications for neurodegeneration.

Air pollution is a major, global public health concern. A growing body of evidence shows that exposure to air pollutants may impair the brain. Living in highly polluted areas has been linked to several neurodegenerative diseases, where exposure to complex mixtures of air pollutants in urban environments may have harmful effects on brain function. These harmful effects are thought to originate from elevated inflammation and oxidative stress. The olfactory epithelium is a key entry site of air pollutants into the brain as the particles are deposited in the upper airways and the nasal region. A potential source of patient-derived cells for study of air pollutant effects is the olfactory mucosa, which constitutes a central part of the olfactory epithelium. This review first summarizes the current literature on the available in vitro models of the olfactory epithelium. It then describes how alterations of the olfactory mucosa are linked to neurodegeneration and discusses potential therapeutic applications of these cells for neurodegenerative diseases. Finally, it reviews the research performed on the effects of air pollutant exposure in cells of the olfactory epithelium. Patient-derived olfactory epithelial models hold great promise for not only elucidating the molecular and cellular pathophysiology of neurodegenerative disorders, but for providing key understanding about air pollutant particle entry and effects at this key brain entry site.

HX600, a synthetic agonist for RXR-Nurr1 heterodimer complex, prevents ischemia-induced neuronal damage.

Ischemic stroke is amongst the leading causes of death and disabilities. The available treatments are suitable for only a fraction of patients and thus novel therapies are urgently needed. Blockage of one of the cerebral arteries leads to massive and persisting inflammatory reaction contributing to the nearby neuronal damage. Targeting the detrimental pathways of neuroinflammation has been suggested to be beneficial in conditions of ischemic stroke. Nuclear receptor 4A-family (NR4A) member Nurr1 has been shown to be a potent modulator of harmful inflammatory reactions, yet the role of Nurr1 in cerebral stroke remains unknown. Here we show for the first time that an agonist for the dimeric transcription factor Nurr1/retinoid X receptor (RXR), HX600, reduces microglia expressed proinflammatory mediators and prevents inflammation induced neuronal death in in vitro co-culture model of neurons and microglia. Importantly, HX600 was protective in a mouse model of permanent middle cerebral artery occlusion and alleviated the stroke induced motor deficits. Along with the anti-inflammatory capacity of HX600 in vitro, treatment of ischemic mice with HX600 reduced ischemia induced Iba-1, p38 and TREM2 immunoreactivities, protected endogenous microglia from ischemia induced death and prevented leukocyte infiltration. These anti-inflammatory functions were associated with reduced levels of brain lysophosphatidylcholines (lysoPCs) and acylcarnitines, metabolites related to proinflammatory events. These data demonstrate that HX600 driven Nurr1 activation is beneficial in ischemic stroke and propose that targeting Nurr1 is a novel candidate for conditions involving neuroinflammatory component.

X-ray fluorescence imaging reveals subcellular biometal disturbances in a childhood neurodegenerative disorder.

Biometals such as zinc, iron, copper and calcium play key roles in diverse physiological processes in the brain, but can be toxic in excess. A hallmark of neurodegeneration is a failure of homeostatic mechanisms controlling the concentration and distribution of these elements, resulting in overload, deficiency or mislocalization. A major roadblock to understanding the impact of altered biometal homeostasis in neurodegenerative disease is the lack of rapid, specific and sensitive techniques capable of providing quantitative subcellular information on biometal homeostasis in situ. Recent advances in X-ray fluorescence detectors have provided an opportunity to rapidly measure biometal content at subcellular resolution in cell populations using X-ray Fluorescence Microscopy (XFM). We applied this approach to investigate subcellular biometal homeostasis in a cerebellar cell line isolated from a natural mouse model of a childhood neurodegenerative disorder, the CLN6 form of neuronal ceroid lipofuscinosis, commonly known as Batten disease. Despite no global changes to whole cell concentrations of zinc or calcium, XFM revealed significant subcellular mislocalization of these important biological second messengers in cerebellar Cln6nclf (CbCln6nclf ) cells. XFM revealed that nuclear-to-cytoplasmic trafficking of zinc was severely perturbed in diseased cells and the subcellular distribution of calcium was drastically altered in CbCln6nclf cells. Subtle differences in the zinc K-edge X-ray Absorption Near Edge Structure (XANES) spectra of control and CbCln6nclf cells suggested that impaired zinc homeostasis may be associated with an altered ligand set in CbCln6nclf cells. Importantly, a zinc-complex, ZnII(atsm), restored the nuclear-to-cytoplasmic zinc ratios in CbCln6nclf cells via nuclear zinc delivery, and restored the relationship between subcellular zinc and calcium levels to that observed in healthy control cells. ZnII(atsm) treatment also resulted in a reduction in the number of calcium-rich puncta observed in CbCln6nclf cells. This study highlights the complementarities of bulk and single cell analysis of metal content for understanding disease states. We demonstrate the utility and broad applicability of XFM for subcellular analysis of perturbed biometal metabolism and mechanism of action studies for novel therapeutics to target neurodegeneration.

Attachment patterns and working alliance in trauma therapy for victims of political violence.

We examined the development of alliance in therapy in different attachment groups in a naturalistic setting. The participants were 36 self-referred Palestinian political ex-prisoners, who were victims of torture and ill treatment and had sought psychotherapy. Their therapy lasted for 10-12 months. The analyses showed that the development of alliance during therapy followed different patterns across the attachment groups. Yet early alliance did not differ between the groups. For the autonomous individuals, alliance dropped in the middle of therapy, and increased back to its initial level by the end. Similarly, for the preoccupied individuals alliance decreased steeply in the middle of the therapy, and then increased even more steeply by the end. In contrast, for the dismissing individuals, alliance was approximately the same at the beginning and in the middle of the therapy, and then it decreased at the end.