Amyloid beta-peptide Abeta(1-42) but not Abeta(1-40) attenuates synaptic AMPA receptor function

The brains of Alzheimer's disease (AD) patients have large numbers of plaques that contain amyloid beta (Abeta) peptides which are believed to play a pivotal role in AD pathology. Several lines of evidence have established the inhibitory role of Abeta peptides on hippocampal memory encoding, a process that relies heavily on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function. In this study the modulatory effects of the two major Abeta peptides, Abeta(1-40) and Abeta(1-42), on synaptic AMPA receptor function was investigated utilizing the whole cell patch clamp technique and analyses of single channel properties of synaptic AMPA receptors. Bath application of Abeta(1-42) but not Abeta(1-40) reduced both the amplitude and frequency of AMPA receptor mediated excitatory postsynaptic currents in hippocampal CA1 pyramidal neurons by approximately 60% and approximately 45%, respectively, in hippocampal CA1 pyramidal neurons. Furthermore, experiments with single synaptic AMPA receptors reconstituted in artificial lipid bilayers showed that Abeta(1-42) reduced the channel open probability by approximately 42% and channel open time by approximately 65% and increased the close times by several fold. Abeta(1-40), however, did not show such inhibitory effects on single channel properties. Application of the reverse sequence peptide Abeta(42-1) also did not alter the mEPSC or single channel properties. These results suggest that Abeta(1-42) but not Abeta(1-40) closely interacts with and exhibits inhibitory effects on synaptic AMPA receptors and may contribute to the memory impairment observed in AD.     

Metabolic effects of oral versus transdermal estrogen in growth hormone-treated girls with turner syndrome

BACKGROUND: Transdermal (TD) estrogen is often preferred over the oral route in postmenopausal and GH-deficient women taking estrogen, but this has not been studied in detail in girls. OBJECTIVE: Our objective was to study the metabolic effects of oral vs. TD estrogen in GH-treated girls with Turner syndrome. DESIGN AND METHODS: Eleven girls with Turner syndrome, mean age 13.4 +/- 0.5 (se) yr, on GH for at least 6 months were recruited. Studies included [(13)C]leucine and d5-glycerol infusions, indirect calorimetry, dual-emission x-ray absorptiometry, and hormone and substrate measurements. They received, in random order, 17beta-estradiol orally (0.5, 1, and 2 mg for 2 wk each) and TD (0.025, 0.0375, and 0.05 mg for 2 wk each), and studies were repeated after each 6-wk course with 4 wk washout in between. RESULTS: Rates of whole-body protein turnover, oxidation and synthesis, lipolysis, lipid and carbohydrate oxidation, and resting energy expenditure were unaffected by either form of estrogen; nor were lipids, insulin, and fibrinogen concentrations affected. Plasma IGF-I concentrations did not change clinically significantly with either form of estrogen, despite higher estrogen concentrations after oral estrogen. Estradiol concentrations did not correlate with any variables measured. CONCLUSIONS: In GH-treated girls with Turner syndrome, neither oral nor TD estrogen adversely affected rates of protein turnover, lipolysis, and lipid oxidation rates or plasma lipids, fibrinogen, or fasting insulin concentrations. There was no clinically significant change in IGF-I concentrations after either form of estrogen. In aggregate, these data suggest that the route of delivery of estrogen does not adversely affect these metabolic effects of GH in young girls with Turner syndrome.     

Electrospun nanostructured scaffolds for bone tissue engineering

The current challenge in bone tissue engineering is to fabricate a bioartificial bone graft mimicking the extracellular matrix (ECM) with effective bone mineralization, resulting in the regeneration of fractured or diseased bones. Biocomposite polymeric nanofibers containing nanohydroxyapatite (HA) fabricated by electrospinning could be promising scaffolds for bone tissue engineering. Nanofibrous scaffolds of poly-l-lactide (PLLA, 860 ± 110 nm), PLLA/HA (845 ± 140 nm) and PLLA/collagen/HA (310 ± 125 nm) were fabricated, and the morphology, chemical and mechanical characterization of the nanofibers were evaluated using scanning electron microscopy, Fourier transform infrared spectroscopy and tensile testing, respectively. The in vitro biocompatibility of different nanofibrous scaffolds was also assessed by growing human fetal osteoblasts (hFOB), and investigating the proliferation, alkaline phosphatase activity (ALP) and mineralization of cells on different nanofibrous scaffolds. Osteoblasts were found to adhere and grow actively on PLLA/collagen/HA nanofibers with enhanced mineral deposition of 57% higher than the PLLA/HA nanofibers. The synergistic effect of the presence of an ECM protein, collagen and HA in PLLA/collagen/HA nanofibers provided cell recognition sites together with apatite for cell proliferation and osteoconduction necessary for mineralization and bone formation. The results of our study showed that the biocomposite PLLA/collagen/HA nanofibrous scaffold could be a potential substrate for the proliferation and mineralization of osteoblasts, enhancing bone regeneration.     

Coordinated regulation of polycomb group complexes through microRNAs in cancer

Polycomb Repressive Complexes (PRC1 and PRC2)-mediated epigenetic regulation is critical for maintaining cellular homeostasis. Members of Polycomb Group (PcG) proteins including EZH2, a PRC2 component, are upregulated in various cancer types, implicating their role in tumorigenesis. Here, we have identified several microRNAs (miRNAs) that are repressed by EZH2. These miRNAs, in turn, regulate the expression of PRC1 proteins BMI1 and RING2. We found that ectopic overexpression of EZH2-regulated miRNAs attenuated cancer cell growth and invasiveness, and abrogated cancer stem cell properties. Importantly, expression analysis revealed an inverse correlation between miRNA and PRC protein levels in cell culture and prostate cancer tissues. Taken together, our data have uncovered a coordinate regulation of PRC1 and PRC2 activities that is mediated by miRNAs.     

Methamphetamine-induced neurotoxicity: the road to Parkinson’s disease

Studies have implicated methamphetamine exposure as a contributor to the development of Parkinson’s disease. There is a significant degree of striatal dopamine depletion produced by methamphetamine, which makes the toxin useful in the creation of an animal model of Parkinson’s disease. Parkinson’s disease is a progressive neurodegenerative disorder associated with selective degeneration of nigrostriatal dopaminergic neurons. The immediate need is to understand the substances that increase the risk for this debilitating disorder as well as these substances’ neurodegenerative mechanisms. Currently, various approaches are being taken to develop a novel and cost-effective anti-Parkinson’s drug with minimal adverse effects and the added benefit of a neuroprotective effect to facilitate and improve the care of patients with Parkinson’s disease. A methamphetamine-treated animal model for Parkinson’s disease can help to further the understanding of the neurodegenerative processes that target the nigrostriatal system. Studies on widely used drugs of abuse, which are also dopaminergic toxicants, may aid in understanding the etiology, pathophysiology and progression of the disease process and increase awareness of the risks involved in such drug abuse. In addition, this review evaluates the possible neuroprotective mechanisms of certain drugs against methamphetamine-induced toxicity.     

Amyloid beta peptides and glutamatergic synaptic dysregulation

Alzheimer's disease (AD) is a major neurodegenerative disorder in which overproduction and accumulation of amyloid beta (Abeta) peptides result in synaptic dysfunction. Recent reports strongly suggest that in the initial stages of AD glutamate receptors are dysregulated by Abeta accumulation resulting in disruption of glutamatergic synaptic transmission which parallels early cognitive deficits. In the presence of Abeta, 2-amino-3-(3-hydoxy-5-methylisoxazol-4-yl) propionic acid (AMPA) glutamate receptor function is disrupted and the surface expression is reduced. Abeta has also been shown to modulate N-methyl-d-aspartate receptors (NMDARs) and metabotropic glutamate receptors. The Abeta mediated glutamate receptor modifications can lead to synaptic dysfunction resulting in excitotoxic neurodegeneration during the progression of AD. This review discusses the recent findings that glutamatergic signaling could be compromised by Abeta induced modulation of synaptic glutamate receptors in specific brain regions.     

Integrative genomics analysis reveals silencing of beta-adrenergic signaling by polycomb in prostate cancer

The Polycomb group (PcG) protein EZH2 possesses oncogenic properties for which the underlying mechanism is unclear. We integrated in vitro cell line, in vivo tumor profiling, and genome-wide location data to nominate key targets of EZH2. One of the candidates identified was ADRB2 (Adrenergic Receptor, Beta-2), a critical mediator of beta-adrenergic signaling. EZH2 is recruited to the ADRB2 promoter and represses ADRB2 expression. ADRB2 inhibition confers cell invasion and transforms benign prostate epithelial cells, whereas ADRB2 overexpression counteracts EZH2-mediated oncogenesis. ADRB2 is underexpressed in metastatic prostate cancer, and clinically localized tumors that express lower levels of ADRB2 exhibit a poor prognosis. Taken together, we demonstrate the power of integrating multiple diverse genomic data to decipher targets of disease-related genes.