Michael Haaf

Cytokine toxicity to oligodendrocyte precursors is mediated by iron.

Inflammatory processes play a key role in the pathogenesis of a number of common neurodegenerative disorders such as Alzheimers disease (AD), Parkinsons disease (PD), and multiple sclerosis (MS). Abnormal iron accumulation is frequently noted in these diseases and compelling evidence exists that iron is involved in inflammatory reactions. Histochemical stains for iron repeatedly demonstrate that oligodendrocytes, under normal conditions, stain more prominently than any other cell type in the brain. Therefore, we examined the hypothesis that cytokine toxicity to oligodendrocytes is iron mediated. Oligodendrocytes in culture were exposed to interferon‐γ (IFN‐γ), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α). Toxicity was observed in a dose‐dependent manner for IFN‐γ and TNF‐α. IL‐1β was not toxic in the concentrations used in this study. The toxic concentration of IFN‐γ, and TNF‐α was lower if the cells were iron loaded, but iron loading had no effect on the toxicity of IL‐1β. These data provide insight into the controversy regarding the toxicity of cytokines to oligodendrocytes by revealing that iron status of these cells will significantly impact the outcome of cytokine treatment. The exposure of oligodendrocytes to cytokines plus iron decreased mitochondrial membrane potential but activation of caspase 3 is limited. The antioxidant, TPPB, which targets mitochondria, protected the oligodendrocytes from the iron‐mediated cytotoxicity, providing further support that mitochondrial dysfunction may underlie the iron‐mediated cytokine toxicity. Therapeutic strategies involving anti‐inflammatory agents have met with limited success in the treatment of demyelinating disorders. A better understanding of these agents and the contribution of cellular iron status to cytokine toxicity may help develop a more consistent intervention strategy.

Dietary lipophilic iron alters amyloidogenesis and microglial morphology in Alzheimer's disease knock-in APP mice

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized pathologically by amyloid beta (Aβ) deposition, microgliosis, and iron dyshomeostasis. Increased labile iron due to homeostatic dysregulation is believed to facilitate amyloidogenesis. Free iron is incorporated into aggregating amyloid peptides during Aβ plaque formation and increases potential for oxidative stress surrounding plaques. The goal of this work was to observe how brain iron levels temporally influence Aβ plaque formation, plaque iron concentration, and microgliosis. We fed humanized APPNL-F and APPNL-G-F knock-in mice lipophilic iron compound 3,5,5-trimethylhexanoyl ferrocene (TMHF) and iron deficient diets for twelve months. TMHF elevated brain iron by 22% and iron deficiency decreased brain iron 21% relative to control diet. Increasing brain iron with TMHF accelerated plaque formation, increased Aβ staining, and increased senile morphology of amyloid plaques. Increased brain iron was associated with increased plaque-iron loading and microglial iron inclusions. TMHF decreased IBA1+ microglia branch length while increasing roundness indicative of microglial activation. This body of work suggests that increasing mouse brain iron with TMHF potentiates a more human-like Alzheimers disease phenotype with iron integration into Aβ plaques and associated microgliosis.

Rapid-flow synthesis of Zn—Qn complexes: Teaching old ligands new tricks with reactive Na2(HZnEt2)2

A new method involving rapid flow of ligand solutions through a cartridge loaded with crystalline sodium diethylzinc hydride and subsequent isolation of three Zn-hydroxyquinoline complexes is described. The rapid-flow approach allowed the pyrophoric starting material to be used outside of the glovebox atmosphere and enabled fast mixing with ligand solutions for zinc complexation in seconds. The identity of all complexes was established by proton (1H) and carbon (13C) nuclear magnetic resonance (NMR) spectroscopy and single crystal X-ray diffraction.

Magnetic resonance imaging of APP/PS1/Tau mice on gradated iron diets

Background: There is converging evidence that iron overload is involved in both amyloid-beta (Ab) plaque and neurofibrillary tangle (NFT) formation. Our previous results have demonstrated that hypo-intensities on T2and T2*-weighted MRI datasets coincide with Ab plaques in AD and transgenic neural tissue. There are crucial unanswered questions in the current literature on how iron and amyloid fibrils are involved in plaque and tangle genesis in the living brain and the neurotoxic impact of amyloidogenesis. We hypothesize that iron is a cofactor in the genesis of Ab plaques and plays a synergistic function in relation to Ab plaque neurotoxicity. The goal of this research is to 1) determine the in vivo relationship between iron and AD pathology, 2) observe the effects of different iron diets on spatial and learning memory using escape maze tasks, and 3) establish the cyto-architectural basis of AD pathology in relation to MR metrics. Methods: Four groups of six APP/PS1/ Tau transgenic mice were randomized into four diet groups consisting of Fe deficient, 35 mg/kg Fe, 200 mg/kg Fe, and 0.1% lipophilic iron. Mice were scanned on a 7.0 T system at baseline and at three month increments for one year along with cognitive and blood biomarker measures. Group based parametric map analysis and region of interest (ROI) based transverse relaxation metrics were generated. Results: Group based transverse parameter maps and ROI analysis of mice fed the iron diets demonstrate that mice have shorter transverse relaxation in a gradated step-wise fashion with increasing iron diet in the same cortical regions. Conclusions: The parametric group analysis and segmentation changes confirm that high iron diets significantly alter the APP/PS1/Tau brain. Our previous data has shown that transverse relaxation is a measure of plaque formation and iron loading; as such, the cortical relaxation changes are hypothesized to reflect an accumulation of iron and Ab plaques genesis in the cortex. This research will generate new information for understanding the role of homeostatic iron overload in Ab plaque and NFT formation within the AD brain to determine how iron levels affect plaque morphology, pTau formation, iron management, inflammatory response, and cognition. P1-163 MANGANESE-ENHANCED MAGNETIC RESONANCE IMAGING (MEMRI) MEASURES PRE-PATHOLOGICAL NEURONAL DYSFUNCTION BEFORE THE APPEARANCE OF TAU PATHOLOGY IN RTG4510 MICE