CXCR4 involvement in neurodegenerative diseases

Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases

Protein-responsive protein release of supramolecular/polymer hydrogel composite integrating enzyme activation systems

抗体に応答してバイオ医薬を自律的に放出する機能性ゲルを開発 --体内埋め込み型の新たな医療用ソフトデバイスとして期待--. 京都大学プレスリリース. 2020-08-03.Non-enzymatic proteins including antibodies function as biomarkers and are used as biopharmaceuticals in several diseases. Protein-responsive soft materials capable of the controlled release of drugs and proteins have potential for use in next-generation diagnosis and therapies. Here, we describe a supramolecular/agarose hydrogel composite that can release a protein in response to a non-enzymatic protein. A non-enzymatic protein-responsive system is developed by hybridization of an enzyme-sensitive supramolecular hydrogel with a protein-triggered enzyme activation set. In situ imaging shows that the supramolecular/agarose hydrogel composite consists of orthogonal domains of supramolecular fibers and agarose, which play distinct roles in protein entrapment and mechanical stiffness, respectively. Integrating the enzyme activation set with the composite allows for controlled release of the embedded RNase in response to an antibody. Such composite hydrogels would be promising as a matrix embedded in a body, which can autonomously release biopharmaceuticals by sensing biomarker proteins

Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor-γ (PPARγ), which is a nuclear transcriptional regulator. Here we show that PPARγ depletion potentiates β-secretase [β-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARγ, as well as NSAIDs and PPARγ activators, reduced BACE1 gene promoter activity. These results suggested that PPARγ could be a repressor of BACE1. We then identified a PPARγ responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARγ to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARγ gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPARγ agonists increased PPARγ and reduced BACE1 mRNA and intracellular β-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPARγ expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARγ in the modulation of amyloid-β generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARγ and decreased BACE1 gene transcription

Measurement of Cross-sections and Leptonic Forward-backward Asymmetries At the Z-pole and Determination of Electroweak Parameters

We report on the measurement of the leptonic and hadronic cross sections and leptonic forward-backward asymmetries at the Z peak with the L3 detector at LEP. The total luminosity of 40.8 pb-1 collected in the years 1990, 1991 and 1992 corresponds to 1.09 . 10(6) hadronic and 0.98 . 10(5) leptonic Z decays observed. These data allow us to determine the electroweak parameters. From the cross sections we derive the properties of the Z boson: M(Z) = 91 195 +/- 9 MeV GAMMA(Z) = 2494 +/- 10 MeV GAMMA(had) = 1748 +/- 10 MeV GAMMA(l) = 83.49 +/- 0.46 MeV, assuming lepton universality. We obtain an invisible width of GAMMA(inv) = 496.5 +/- 7.9 MeV which, in the Standard Model, corresponds to a number of light neutrino species of N(v) = 2.981 +/- 0.050. Using also the three leptonic forward-backward asymmetries and the average tau polarization, we determine the effective vector and axial-vector coupling constants of the neutral weak current to charged leptons to be: g(V)-l = -0.0378(+0.0045/-0.0042) g(A)-l = -0.4998 +/- 0.0014 Within the framework of the Standard Model, and including our measurements of the Z --> bbBAR forward-backward asymmetry and partial decay width, we derive an effective electroweak mixing angle of sin2 theta(W)BAR = 0.2326 +/- 0.0012. We obtain an estimate for the strong coupling constant, alpha(s) = 0.142 +/- 0.013, and for the top-quark mass, m(t) = 158(+32/-40) +/- 19(Higgs) GeV, where the second error arises due to the uncertainty in the Higgs-boson mass