Beyond Activation: Characterizing Microglial Functional Phenotypes

Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as “resting”, amoeboid and phagocytic microglia were viewed as “activated”. In aged human brains, a fourth, morphologically novel state has been described, i.e., dystrophic microglia, which are thought to be senescent cells. Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances, they seem to have an “expiration date” limiting their capacity to phagocytose and support neurons. Identifying factors that drive microglial aging may thus be helpful to delay the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations. Given the heterogeneity of pathologic states in the central nervous system, the need for accurately describing microglial morphology and expression patterns becomes increasingly important. Here, we review commonly used microglial markers and their fluctuations in expression in health and disease, with a focus on IBA1 low/negative microglia, which can be found in individuals with liver disease

Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease

The role of microglial cells in the pathogenesis of Alzheimer’s disease (AD) neurodegeneration is unknown. Although several works suggest that chronic neuroinflammation caused by activated microglia contributes to neurofibrillary degeneration, anti-inflammatory drugs do not prevent or reverse neuronal tau pathology. This raises the question if indeed microglial activation occurs in the human brain at sites of neurofibrillary degeneration. In view of the recent work demonstrating presence of dystrophic (senescent) microglia in aged human brain, the purpose of this study was to investigate microglial cells in situ and at high resolution in the immediate vicinity of tau-positive structures in order to determine conclusively whether degenerating neuronal structures are associated with activated or with dystrophic microglia. We used a newly optimized immunohistochemical method for visualizing microglial cells in human archival brain together with Braak staging of neurofibrillary pathology to ascertain the morphology of microglia in the vicinity of tau-positive structures. We now report histopathological findings from 19 humans covering the spectrum from none to severe AD pathology, including patients with Down’s syndrome, showing that degenerating neuronal structures positive for tau (neuropil threads, neurofibrillary tangles, neuritic plaques) are invariably colocalized with severely dystrophic (fragmented) rather than with activated microglial cells. Using Braak staging of Alzheimer neuropathology we demonstrate that microglial dystrophy precedes the spread of tau pathology. Deposits of amyloid-beta protein (Aβ) devoid of tau-positive structures were found to be colocalized with non-activated, ramified microglia, suggesting that Aβ does not trigger microglial activation. Our findings also indicate that when microglial activation does occur in the absence of an identifiable acute central nervous system insult, it is likely to be the result of systemic infectious disease. The findings reported here strongly argue against the hypothesis that neuroinflammatory changes contribute to AD dementia. Instead, they offer an alternative hypothesis of AD pathogenesis that takes into consideration: (1) the notion that microglia are neuron-supporting cells and neuroprotective; (2) the fact that development of non-familial, sporadic AD is inextricably linked to aging. They support the idea that progressive, aging-related microglial degeneration and loss of microglial neuroprotection rather than induction of microglial activation contributes to the onset of sporadic Alzheimer’s disease. The results have far-reaching implications in terms of reevaluating current treatment approaches towards AD

Quantum Cryptography

Quantum cryptography could well be the first application of quantum mechanics at the individual quanta level. The very fast progress in both theory and experiments over the recent years are reviewed, with emphasis on open questions and technological issues.Comment: 55 pages, 32 figures; to appear in Reviews of Modern Physic

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis

ZUMABUS 6 (1982)

This omnibus survey has the following main survey focus areas: 1. Questions on use of drugs (moved to study no. ZA5988), 2. Attitude to energy and environmental questions, 3. Occupation and job market, 4. ZUMA standard demography, 5. Miscellaneous Topics: 1. Questions on use of drugs: (moved to study no. ZA5988). 2. Attitude to energy and environmental questions: attitude to energy policies and questions of nuclear energy (scales); supporter or opponent of nuclear energy; attitude to an increased use of coal as energy source; possible areas for use of coal; attitude to coal liquefaction and large power plants; assumed consequential damages for the environment from increased use of coal; alternative energy sources; assumed protests given increased expansion of coal-fired power plants, possible reasons for small or greater readiness to accept coal-fired power plants; attitude to participation in selected protest actions for and against nuclear power plants. 3. Occupation and job market: self-assessment of social class; detailed information on vocational training and employment; characterization of activity exercised primarily; length of company employment; work at place of residence; company size; business size; monthly, weekly or daily payment of salary; achievement-based income; specification of wage or salary group; collective bargaining area; image of one´s company in comparison with other businesses in the vicinity; management duties and size of span of control; personal freedom to decide about start of work; flextime; freedom to decide in establishing work processes; days absent, days of vacation and times of unemployment in the past year; overtime worked and core working hours; general occupational satisfaction and work satisfaction (scale); work satisfaction (scale); demand criteria for an optimum job; recommendations on job improvements made with the works council; mobility readiness with change of job; school training and occupational demands; readiness for further education in occupation; desire for change of job and reasons for remaining at current job; assumed difficulties to find a comparable position after loss of job; number of jobs up to now. Characterization of previous job: reasons for terminating this employment; description of occupational activity; company and business size of this job; management duties and span of control; arrangement of working hours. The following questions were posed to those persons not employed: interest in employment; reason for the desire for work. Unemployed were also asked: length and times of unemployment since 1970. 4. ZUMA standard demography: regional and social origins; school degrees of parents; self-assessment of social class; sources of income; characteristics of one´s own employment and of spouse; extensive recording and encoding of occupation after the ISCO code system; housing situation; religiousness; memberships; local residency; age; sex; marital status; religious denomination; school education; occupation; employment; type of company; income; household size; household composition; interest in politics; city size; state. 5. Miscellaneous: political interest; postmaterialism (scale); occupation activity of spouse; school degree of spouse; social origins; year of birth and month of birth. Interviewer rating: spontaneity of answers given and uncertainty of respondent on the question of personal deviant behavior.Diese Mehrthemen-Erhebung hat folgende Erhebungsschwerpunkte: 1.) Fragen zum Drogenkonsum (in Studie ZA5988 verschoben), 2.) Einstellung zu Energie- und Umweltfragen, 3.) Beruf und Arbeitsmarkt, 4.) ZUMA-Standarddemographie, 5.) Sonstiges Themen: Zu 1.) Fragen zum Drogenkonsum: (in Studie ZA5988 verschoben). Zu 2.) Einstellung zu Energie- und Umweltfragen: Einstellung zur Energiepolitik und Fragen der Kernenergie (Skalen); Befürworter oder Gegner der Kernenergie; Einstellung zu einer verstärkten Nutzung der Kohle als Energieträger; mögliche Einsatzbereiche für Kohle; Einstellung zur Kohleverflüssigung und zu Großkraftwerken; vermutete Folgeschäden einer zunehmenden Kohlenutzung für die Umwelt; alternative Energiequellen; vermutete Proteste bei verstärktem Ausbau von Kohlekraftwerken, mögliche Gründe für eine geringe bzw. größere Akzeptanzbereitschaft für Kohlekraftwerke; Einstellung zur Teilnahme an ausgewählten Protestaktionen für und gegen Kernkraftwerke. Zu 3.) Beruf und Arbeitsmarkt: Selbsteinschätzung der Schichtzugehörigkeit; detaillierte Angaben zu Berufsausbildung und Berufstätigkeit; Charakterisierung der überwiegend ausgeübten Tätigkeit; Dauer der Betriebszugehörigkeit; Arbeitsstätte am Wohnort; Betriebsgröße; Unternehmensgröße; monatliche, wöchentliche oder tägliche Gehaltszahlung; leistungsabhängiges Einkommen; Angabe der Lohn- bzw. Gehaltsgruppe; Tarifgebiet; Image des eigenen Betriebes im Vergleich zu anderen Unternehmen in der Umgebung; Leitungsaufgaben und Größe der Kontrollspanne; eigene Entscheidungsfreiheit über den Arbeitsbeginn; gleitende Arbeitszeit; Entscheidungsfreiheit bei der Festlegung von Arbeitsvorgängen; Fehltage, Urlaubstage und Zeiten der Arbeitslosigkeit im vergangenen Jahr; abgeleistete Überstunden und Regelarbeitszeit; allgemeine Berufszufriedenheit und Arbeitszufriedenheit (Skalometer); Arbeitszufriedenheit (Skala); Anforderungskriterien an einen optimalen Arbeitsplatz; gemachte Vorschläge zur Arbeitsplatzverbesserung beim Betriebsrat; Mobilitätsbereitschaft beim Arbeitsplatzwechsel; Schulausbildung und berufliche Anforderungen; Weiterbildungsbereitschaft im Beruf; Wunsch nach Arbeitsplatzwechsel und Gründe für den Verbleib am jetzigen Arbeitsplatz; vermutete Schwierigkeiten, eine gleichwertige Stellung bei Arbeitsplatzverlust zu finden; Anzahl der bislang innegehabten Arbeitsstellen. Charakterisierung der vorletzten Arbeitsstelle: Gründe für die Aufkündigung dieses Beschäftigungsverhältnisses; Beschreibung der beruflichen Tätigkeit; Betriebs- und Unternehmensgröße dieser Arbeitsstelle; Leitungsaufgaben und Kontrollspanne; Arbeitszeitregelung. Bei nicht im Arbeitsverhältnis stehenden Personen wurde zusätzlich gefragt: Interesse an einer Berufstätigkeit; Grund für den Wunsch nach Arbeit. Bei Arbeitslosen wurde zusätzlich gefragt: Dauer und Zeiten der Arbeitslosigkeit seit 1970. Zu 4.) ZUMA-Standarddemographie: Regionale und soziale Herkunft; Schulabschlüsse der Eltern; Selbsteinschätzung der Schichtzugehörigkeit; Einkommensquellen; Merkmale der eigenen Erwerbstätigkeit und der des Ehepartners; ausführliche Erfassung und Verkodung des Berufs nach dem ISCO-Codesystem; Wohnsituation; Religiosität; Mitgliedschaften; Ortsansässigkeit; Alter; Geschlecht; Familienstand; Konfession; Schulbildung; Beruf; Berufstätigkeit; Art des Betriebs; Einkommen; Haushaltsgröße; Haushaltszusammensetzung; Politikinteresse; Ortsgröße; Bundesland. Zu 5.) Sonstiges: Politisches Interesse; Postmaterialismus (Skala); Berufliche Tätigkeit des Ehepartners; Schulabschluß des Ehepartners; soziale Herkunft; Geburtsjahr und Geburtsmonat. Interviewerrating: Spontanität der Antwortgebung und Unsicherheit des Befragten auf die Frage nach eigenem abweichenden Verhalten

Beyond Activation: Characterizing Microglial Functional Phenotypes

Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as “resting”, amoeboid and phagocytic microglia were viewed as “activated”. In aged human brains, a fourth, morphologically novel state has been described, i.e., dystrophic microglia, which are thought to be senescent cells. Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances, they seem to have an “expiration date” limiting their capacity to phagocytose and support neurons. Identifying factors that drive microglial aging may thus be helpful to delay the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations. Given the heterogeneity of pathologic states in the central nervous system, the need for accurately describing microglial morphology and expression patterns becomes increasingly important. Here, we review commonly used microglial markers and their fluctuations in expression in health and disease, with a focus on IBA1 low/negative microglia, which can be found in individuals with liver disease

Beyond Activation: Characterizing Microglial Functional Phenotypes

Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as “resting”, amoeboid and phagocytic microglia were viewed as “activated”. In aged human brains, a fourth, morphologically novel state has been described, i.e., dystrophic microglia, which are thought to be senescent cells. Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances, they seem to have an “expiration date” limiting their capacity to phagocytose and support neurons. Identifying factors that drive microglial aging may thus be helpful to delay the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations. Given the heterogeneity of pathologic states in the central nervous system, the need for accurately describing microglial morphology and expression patterns becomes increasingly important. Here, we review commonly used microglial markers and their fluctuations in expression in health and disease, with a focus on IBA1 low/negative microglia, which can be found in individuals with liver disease

Beyond Activation: Characterizing Microglial Functional Phenotypes

Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as “resting”, amoeboid and phagocytic microglia were viewed as “activated”. In aged human brains, a fourth, morphologically novel state has been described, i.e., dystrophic microglia, which are thought to be senescent cells. Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances, they seem to have an “expiration date” limiting their capacity to phagocytose and support neurons. Identifying factors that drive microglial aging may thus be helpful to delay the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations. Given the heterogeneity of pathologic states in the central nervous system, the need for accurately describing microglial morphology and expression patterns becomes increasingly important. Here, we review commonly used microglial markers and their fluctuations in expression in health and disease, with a focus on IBA1 low/negative microglia, which can be found in individuals with liver disease