Long-lasting epigenetic microglial memory of peripheral inflammation modulates hallmarks of Alzheimer's disease pathology

Microglia comprise the resident tissue macrophage population in the brain parenchyma. They acquire a variety of functions in health and disease and are thus one of the most studied cell types regarding their contribution to neurological disease. In Alzheimer’s disease, deposition of amyloid-β occurs in senile plaques and leads to alterations of the microglial phenotype. This feature is mimicked in transgenic mouse models developing cerebral β-amyloidosis. How microglia influence onset and progression of Alzheimer’s disease remains incompletely understood despite many studies. Microglia are developmentally distinct from tissue macrophages in other organs and invade the brain early in embryogenesis. A long lifetime has been attributed to microglia; however, this has only scarcely been studied. Today, technological advances in the development of transgenic mouse models and in vivo microscopy allow for the in depth analysis of microglial turnover. In the first study presented here, we used genetic tools to label individual microglia and followed them in vivo by two-photon imaging. Long-term imaging over many months revealed that microglia are a long-lived cell population with low turnover rates. Furthermore, the rates of microglial proliferation and death were equal, matching previous reports that microglial cell numbers stay stable over time. In line with previous studies, higher proliferation rates were found in a mouse model of cerebral β-amyloidosis. Nevertheless, both in health and disease conditions, microglia lived many months and a proportion of microglia persisted throughout the entire lifespan of mice. The long lifetime of microglia renders them suitable for the characterization of innate immune memory, a recently emerged concept, in the brain. While it was previously believed that only adaptive immune cells depict memory characteristics, recent reports have demonstrated immune memory also in cells of the innate immune system. Herein, a priming immune stimulus leads to a long-lasting change in the activation state of the innate immune cell, thereby modifying its response towards a secondary stimulus. In particular, two paradigms can be distinguished: a heightened response has been termed training, while a reduced response is called tolerance. Our second study aimed to reveal whether training and tolerance are inducible in the brain and could be long-lasting modifiers of later occurring neurological disease pathology. We demonstrate that following peripheral immune stimulation with lipopolysaccharides or certain cytokines acute training and tolerance effects were evident in the brain. Furthermore, training and tolerance had opposing effects on much later occurring neuropathology of stroke and early stages of cerebral β-amyloidosis. Microglial enhancer landscape, gene expression, and function differed in response to peripheral immune stimulation with lipopolysaccharides, indicating long-term microglial reprogramming. Therefore, our study provides evidence for long-lasting innate immune memory in microglia that is epigenetically encoded and is sufficient to alter later developing neuropathology. In the third study, we investigated whether training and tolerance modify amyloid plaque structure and neurotoxicity in mice with more advanced cerebral β-amyloidosis. Strikingly, modifications of amyloid plaque structure were evident 9 months after induction of training and tolerance, and occurred concomitantly with alterations in microglial function. In particular, peripheral training and tolerance stimuli altered the phenotype of plaque-associated microglia or reduced their number, respectively. Both impaired microglial barrier function, a recently described feature of microglia around amyloid plaques in Alzheimer’s disease mouse models and patients. Importantly, modulation of microglial function, as induced by peripheral immune stimulation, altered amyloid plaque structure and thereby increased plaque-associated neurotoxicity. These results indicate that changes in microglial function contribute to neuronal damage by modulating amyloid structure and that such changes may occur in response to peripheral inflammatory events. In summary, this thesis demonstrates that microglia are exceptionally long-lived cells with the capability to form persisting immune memory. Peripheral immune stimulation epigenetically reprograms microglia to acquire distinct phenotypes that subsequently modify pathological features of cerebral β-amyloidosis. Therefore, we identified epigenetic microglial memory of peripheral inflammation as an essential modifier of neurological diseases

Contested Territory: Regional Development in France, 1934-1968

This thesis shows how government intervention shaped the remapping of industry and population in postwar France. Combining a national perspective with local case studies, it analyzes the regional development programs organized around the new conceptual framework of aménagement du territoire. I address a core tension: industrial decentralization was a Keynesian social policy, which brought new jobs to impoverished areas, but it also undercut the power of Parisian labor and created a kaleidoscope of new regional inequalities. Three chapters trace the complex relationship between projects of urban "containment," rural preservation, and new ideals of Keynesian modernization from 1934 to 1955. I examine the decentralization of defense industries, programs to deindustrialize Paris, and battles to control provincial labor markets during new development. The following two chapters address, respectively, the institutional and discursive bases of redistributive regional policies and the role of decolonization in shaping debates on inequalities in France. Next, I take the Citroën car factory built in Rennes, Brittany, as a case study of new rural industrialization from Rennes' pro-growth municipal politics to the company's recruitment of peasant workers and the community's contestation of its new employer. A concluding chapter covers key shifts in French industry during the 1960s: Parisian contraction, branch-plant expansion, and new high-tech metropolises. This dissertation is at the junction of social science research-on industrial geography and territorial governance-and the history of French industry and labor, urban policy, and state economic intervention

Orthogonal, metal-free surface modification by strain-promoted azide–alkyne and nitrile oxide–alkene/alkyne cycloadditions

In this article we present a fast and efficient methodology for biochemical surface patterning under extremely mild conditions. Micropatterned azide/benzaldoxime-surfaces were prepared by microcontact printing of a heterobifunctional cyclooctyne oxime linker on azide-terminated self-assembled monolayers (SAMs). Strain-promoted azide–alkyne cycloaddition (SPAAC) in combination with microcontact printing allows fast and effective surface patterning. The resulting bifunctional azide/oxime substrates could successfully be used for metal-free, orthogonal immobilization of various biomolecules by 1,3-dipolar cycloadditions at room temperature. Azide-decorated areas were modified by reaction with a cyclooctyne-conjugate using SPAAC, while benzaldoxime-decorated areas were activated by in situ oxidation to the reactive nitrile oxides and subsequent nitrile oxide cycloaddition with alkene- and alkyne-functionalized bioconjugates. In addition, orthogonal double immobilization was achieved by consecutive and independent SPAAC and nitrile oxide cycloadditions

Electronic Computing Gage System for Monitoring Assembly Operations

An electronic computing gage with IBM card punch was found to be a practical system for monitoring the critical steps in the crimping process of the assembly of some parts. In the crimping process a plastic part is compressed into a metal cup to obtain an assembled component without gaps. Dimensional data of the plastic part and metal cup are recorded on a printed tape and on IBM cards, which are used to program a computer to calculate the standard deviation of the lot. Lot acceptance is statistical and is based on the standard deviation of the lot. The electronic computing gage compares the height of the assembled components before and after crimping and indicates whether or not an acceptable assembly (without gaps) has been made. This system eliminates the need for the manual calculation of height and recording of data at the production site, thereby increasing the reliability of the assembly process at a decrease in cost

Academic Integrity as a Learning Opportunity for Our Students

Poster presented at 2016 E.C. Moore Symposiu

A Generic Strategy for Co‐Presentation of Heparin‐Binding Growth Factors Based on CVD Polymerization

A multifunctional copolymer with both aldehyde and alkyne groups is synthesized by chemical vapor deposition (CVD) for orthogonal co‐immobilization of biomolecules. Surface analytical methods including FTIR and XPS are used to confirm the surface modification. Heparin‐binding growth factors [basic fibroblast growth factor (bFGF) in this study] can be immobilized through interaction with heparin, which was covalently attached to the CVD surface through an aldehyde‐hydrazide reaction. In parallel, an alkyne–azide reaction is used to orthogonally co‐immobilize an adhesion peptide as the second biomolecule. A generic strategy for immobilizing heparin‐binding growth factors on multifunctional chemical vapor deposition copolymer has been developed. Heparin is covalently attached to the aldehyde‐functionalized surface through a carbohydrazide linker. The growth factor then binds directly to the heparin. The alkyne group can then be used to orthogonally immobilize other biomolecule, such as azido‐functionalized adhesion peptides.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93760/1/1459_ftp.pd

Fibrillation of chain branched poly (lactic acid) with improved blood compatibility and bionic structure

YesHighly-oriented poly (lactic acid) (PLA) with bionic fibrillar structure and micro-grooves was fabricated through solid hot drawing technology for further improving the mechanical properties and blood biocompatibility of PLA as blood-contacting medical devices. In order to enhance the melt strength and thus obtain high orientation degree, PLA was first chain branched with pentaerythritol polyglycidyl ether (PGE). The branching degree as high as 12.69 mol% can be obtained at 0.5 wt% PGE content. The complex viscosity, elastic and viscous modulus for chain branched PLA were improved resulting from the enhancement of molecular entanglement, and consequently higher draw ratio can be achieved during the subsequent hot stretching. The stress-induced crystallization of PLA occurred during stretching, and the crystal structure of the oriented PLA can be attributed to the α′ crystalline form. The tensile strength and modulus of PLA were improved dramatically by drawing. Chain branching and orientation could significantly enhance the blood compatibility of PLA by prolonging clotting time and decreasing hemolysis ratio, protein adsorption and platelet activation. Fibrous structure as well as micro-grooves can be observed for the oriented PLA which were similar to intimal layer of blood vessel, and this bionic structure was considered to be beneficial to decrease the activation and/or adhesion of platelets

Sequence-selective detection of double-stranded DNA sequences using pyrrole-imidazole polyamide microarrays

We describe a microarray format that can detect double-stranded DNA sequences with a high degree of sequence selectivity. Cyclooctyne-derivatized pyrrole-imidazole polyamides were immobilized on azide-modified glass substrates using microcontact printing and a strain-promoted azide-alkyne cycloaddition (SPAAC) reaction. These polyamide-immobilized substrates selectively detected a seven-base-pair binding site incorporated within a double-stranded oligodeoxyribonucleotide sequence even in the presence of an excess of a sequence with a single-base-pair mismatc