Inflammation subsequent to mild iron excess differentially alters regional brain iron metabolism, oxidation and neuroinflammation status in mice.

Iron dyshomeostasis and neuroinflammation, characteristic features of the aged brain, and exacerbated in neurodegenerative disease, may induce oxidative stress-mediated neurodegeneration. In this study, the effects of potential priming with mild systemic iron injections on subsequent lipopolysaccharide (LPS)-induced inflammation in adult C57Bl/6J mice were examined. After cognitive testing, regional brain tissues were dissected for iron (metal) measurements by total reflection X-ray fluorescence and synchrotron radiation X-Ray fluorescence-based elemental mapping; and iron regulatory, ferroptosis-related, and glia-specific protein analysis, and lipid peroxidation by western blotting. Microglial morphology and astrogliosis were assessed by immunohistochemistry. Iron only treatment enhanced cognitive performance on the novel object location task compared with iron priming and subsequent LPS-induced inflammation. LPS-induced inflammation, with or without iron treatment, attenuated hippocampal heme oxygenase-1 and augmented 4-hydroxynonenal levels. Conversely, in the cortex, elevated ferritin light chain and xCT (light chain of System Xc-) were observed in response to LPS-induced inflammation, without and with iron-priming. Increased microglial branch/process lengths and astrocyte immunoreactivity were also increased by combined iron and LPS in both the hippocampus and cortex. Here, we demonstrate iron priming and subsequent LPS-induced inflammation led to iron dyshomeostasis, compromised antioxidant function, increased lipid peroxidation and altered neuroinflammatory state in a brain region-dependent manner.

Cysteine string protein alpha accumulates with early pre-synaptic dysfunction in Alzheimer's disease.

In Alzheimer's disease, synapse loss causes memory and cognitive impairment. However, the mechanisms underlying synaptic degeneration in Alzheimer's disease are not well understood. In the hippocampus, alterations in the level of cysteine string protein alpha, a molecular co-chaperone at the pre-synaptic terminal, occur prior to reductions in synaptophysin, suggesting that it is a very sensitive marker of synapse degeneration in Alzheimer's. Here, we identify putative extracellular accumulations of cysteine string alpha protein, which are proximal to beta-amyloid deposits in post-mortem human Alzheimer's brain and in the brain of a transgenic mouse model of Alzheimer's disease. Cysteine string protein alpha, at least some of which is phosphorylated at serine 10, accumulates near the core of beta-amyloid deposits and does not co-localize with hyperphosphorylated tau, dystrophic neurites or glial cells. Using super-resolution microscopy and array tomography, cysteine string protein alpha was found to accumulate to a greater extent than other pre-synaptic proteins and at a comparatively great distance from the plaque core. This indicates that cysteine string protein alpha is most sensitive to being released from pre-synapses at low concentrations of beta-amyloid oligomers. Cysteine string protein alpha accumulations were also evident in other neurodegenerative diseases, including some fronto-temporal lobar dementias and Lewy body diseases, but only in the presence of amyloid plaques. Our findings are consistent with suggestions that pre-synapses are affected early in Alzheimer's disease, and they demonstrate that cysteine string protein alpha is a more sensitive marker for early pre-synaptic dysfunction than traditional synaptic markers. We suggest that cysteine string protein alpha should be used as a pathological marker for early synaptic disruption caused by beta-amyloid.

Low Cerebrospinal Fluid Levels of Melanotransferrin Are Associated With Conversion of Mild Cognitively Impaired Subjects to Alzheimer's Disease.

The disruption of iron metabolism and iron transport proteins have been implicated in the pathogenesis of Alzheimer's disease (AD). Serum melanotransferrin (MTf), a transferrin homolog capable of reversibly binding iron, has been proposed as a biochemical marker of AD. MTf has also been shown to be elevated in iron-rich reactive microglia near amyloid plaques in AD. We examined the association of CSF MTf to hippocampal volumes and cognitive tests in 86 cognitively normal, 135 mild cognitive impairment (MCI) and 66 AD subjects. CSF was collected at baseline for MTf, Aß, total-tau and phosphorylated-tau measurements. Serial cognitive testing with ADAS-Cog13, Rey's auditory visual learning test (RAVLT), mini-mental state examination (MMSE) were performed alongside hippocampal MRI volumetric analysis for up to 10 years after baseline measurements. High levels of baseline CSF MTf were positively associated with baseline hippocampal volume (R 2 = 22%, ß = 0.202, and p = 0.017) and RAVLT scores (R 2 = 7.30%, ß = -0.178, and p = 0.043) and negatively correlated to ADAS-Cog13 (R 2 = 17.3%, ß = 0.247, and p = 0.003) scores in MCI subjects. Interestingly, MCI subjects that converted to AD demonstrated significantly lower levels of CSF MTf (p = 0.020) compared to MCI non-converters at baseline. We suggest the diminished CSF MTf observed in MCI-converters to AD may arise from impaired transport of MTf from blood into the brain tissue/CSF and/or increased MTf export from the CSF into the blood arising from attenuated competition with reduced levels of CSF Aß. Further investigations are required to determine the source of CSF MTf and how brain MTf is regulated by cellular barriers, Aß and activated microglia that surround plaques in AD pathophysiology. In conclusion, low CSF MTf may identify those MCI individuals at risk of converting to AD.

High-Intensity Focused Ultrasound (HIFU) in Uterine Fibroid Treatment: Review Study.

BACKGROUND: High-intensity focused ultrasound (HIFU) is a highly precise medical procedure used locally to heat and destroy diseased tissue through ablation. This study intended to review HIFU in uterine fibroid therapy, to evaluate the role of HIFU in the therapy of leiomyomas as well as to review the actual clinical activities in this field including efficacy and safety measures beside the published clinical literature. MATERIAL/METHODS: An inclusive literature review was carried out in order to review the scientific foundation, and how it resulted in the development of extracorporeal distinct devices. Studies addressing HIFU in leiomyomas were identified from a search of the Internet scientific databases. The analysis of literature was limited to journal articles written in English and published between 2000 and 2013. RESULTS: In current gynecologic oncology, HIFU is used clinically in the treatment of leiomyomas. Clinical research on HIFU therapy for leiomyomas began in the 1990s, and the majority of patients with leiomyomas were treated predominantly with HIFUNIT 9000 and prototype single focus ultrasound devices. HIFU is a non-invasive and highly effective standard treatment with a large indication range for all sizes of leiomyomas, associated with high efficacy, low operative morbidity and no systemic side effects. CONCLUSIONS: Uterine fibroid treatment using HIFU was effective and safe in treating symptomatic uterine fibroids. Few studies are available in the literature regarding uterine artery embolization (UAE). HIFU provides an excellent option to treat uterine fibroids.