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Telomere microglia

Björn Spittau
Aging of the central nervous system (CNS) is one of the major risk factors for the development of neurodegenerative pathologies such as Parkinson's disease (PD) and Alzheimer's disease (AD). The molecular mechanisms underlying the onset of AD and especially PD are not well understood. However, neuroinflammatory responses mediated by microglia as the resident immune cells of the CNS have been reported for both diseases. The unique nature and developmental origin of microglia causing microglial self-renewal and telomere shortening led to the hypothesis that these CNS-specific innate immune cells become senescent...
2017: Frontiers in Aging Neuroscience
Golo Kronenberg, Ria Uhlemann, Johanna Schöner, Stephanie Wegner, Valérie Boujon, Nikolas Deigendesch, Matthias Endres, Karen Gertz
Microglia senescence may promote neuropsychiatric disease. This prompted us to examine the relationship between microglia activation states and telomere biology. A panel of candidate genes associated with telomere maintenance, mitochondrial biogenesis, and cell-cycle regulation were investigated in M1- and M2-polarized microglia in vitro as well as in MACS-purified CD11b+ microglia/brain macrophages from models of stroke, Alzheimer's disease, and chronic stress. M1 polarization, ischemia, and Alzheimer pathology elicited a strikingly similar transcriptomic profile with, in particular, reduced expression of murine Tert...
August 2017: European Archives of Psychiatry and Clinical Neuroscience
Annika Scheffold, Inge R Holtman, Sandra Dieni, Nieske Brouwer, Sarah-Fee Katz, Billy Michael Chelliah Jebaraj, Philipp J Kahle, Bastian Hengerer, André Lechel, Stephan Stilgenbauer, Erik W G M Boddeke, Bart J L Eggen, Karl-Lenhard Rudolph, Knut Biber
Parkinson's disease is one of the most common neurodegenerative disorders of the elderly and ageing hence described to be a major risk factor. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of ageing. The role of telomere dysfunction in neurological diseases and the ageing brain is not clarified and there is an ongoing discussion whether telomere shortening is linked to Parkinson's disease. Here we studied a mouse model of Parkinson's disease (Thy-1 [A30P] α-synuclein transgenic mouse model) in the background of telomere shortening (Terc knockout mouse model)...
August 22, 2016: Acta Neuropathologica Communications
Birgit Linkus, Diana Wiesner, Martina Meßner, Alexander Karabatsiakis, Annika Scheffold, K Lenhard Rudolph, Dietmar R Thal, Jochen H Weishaupt, Albert C Ludolph, Karin M Danzer
Telomere shortening has been linked to a variety of neurodegenerative diseases. Recent evidence suggests that reduced telomerase expression results in shorter telomeres in leukocytes from sporadic patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. Here, we have characterized telomere length in microglia, astroglia and neurons in human post mortem brain tissue from ALS patients and healthy controls. Moreover, we studied the consequences of telomerase deletion in a genetic mouse model for ALS...
February 2016: Aging
Gustav Nilsonne, Sandra Tamm, Kristoffer N T Månsson, Torbjörn Åkerstedt, Mats Lekander
Leukocyte telomere length has been shown to correlate to hippocampus volume, but effect estimates differ in magnitude and are not uniformly positive. This study aimed primarily to investigate the relationship between leukocyte telomere length and hippocampus gray matter volume by meta-analysis and secondarily to investigate possible effect moderators. Five studies were included with a total of 2107 participants, of which 1960 were contributed by one single influential study. A random-effects meta-analysis estimated the effect to r = 0...
2015: F1000Research
Divya D A Raj, Jill Moser, Susanne M A van der Pol, Ronald P van Os, Inge R Holtman, Nieske Brouwer, Hisko Oeseburg, Wandert Schaafsma, Evelyn M Wesseling, Wilfred den Dunnen, Knut P H Biber, Helga E de Vries, Bart J L Eggen, Hendrikus W G M Boddeke
Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first-generation G1 mTerc(-/-) )- and late-generation (third-generation G3 and G4 mTerc(-/-) ) telomerase-deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc)...
December 2015: Aging Cell
Asif Manzoor Khan, Alicia A Babcock, Hamid Saeed, Christa Løth Myhre, Moustapha Kassem, Bente Finsen
The susceptibility of the aging brain to neurodegenerative disease may in part be attributed to cellular aging of the microglial cells that survey it. We investigated the effect of cellular aging induced by telomere shortening on microglia by the use of mice lacking the telomerase RNA component (TERC) and design-based stereology. TERC knockout (KO) mice had a significantly reduced number of CD11b(+) microglia in the dentate gyrus. Because of an even greater reduction in dentate gyrus volume, microglial density was, however, increased...
June 2015: Neurobiology of Aging
Alison Spilsbury, Satomi Miwa, Johannes Attems, Gabriele Saretzki
The telomerase reverse transcriptase protein TERT has recently been demonstrated to have a variety of functions both in vitro and in vivo, which are distinct from its canonical role in telomere extension. In different cellular systems, TERT protein has been shown to be protective through its interaction with mitochondria. TERT has previously been found in rodent neurons, and we hypothesize that it might have a protective function in adult human brain. Here, we investigated the expression of TERT at different stages of Alzheimer's disease pathology (Braak Stages I-VI) in situ and the ability of TERT to protect against oxidative damage in an in vitro model of tau pathology...
January 28, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Tanja Hochstrasser, Josef Marksteiner, Michaela Defrancesco, Eberhard A Deisenhammer, Georg Kemmler, Christian Humpel
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. In AD, monocytes migrate across the blood-brain barrier and differentiate into microglia, are linked to inflammatory responses and display age-dependent decreases in telomere lengths. METHODS: Six monocyte-specific chemokines and the (telomere-associated) tumor suppressor proteins p53 and p21 were determined by multiplex immunoassay in plasma and monocyte extracts of patients with AD or mild cognitive impairment, and levels were compared between patients and controls (without cognitive impairment)...
January 2011: Dementia and Geriatric Cognitive Disorders Extra
Harshvardhan Rolyan, Annika Scheffold, Annette Heinrich, Yvonne Begus-Nahrmann, Britta Heike Langkopf, Sabine M Hölter, Daniela M Vogt-Weisenhorn, Birgit Liss, Wolfgang Wurst, Dieter Chichung Lie, Dietmar Rudolf Thal, Knut Biber, Karl Lenhard Rudolph
Alzheimer's disease is a neurodegenerative disorder of the elderly and advancing age is the major risk factor for Alzheimer's disease development. Telomere shortening represents one of the molecular causes of ageing that limits the proliferative capacity of cells, including neural stem cells. Studies on telomere lengths in patients with Alzheimer's disease have revealed contrary results and the functional role of telomere shortening on brain ageing and Alzheimer's disease is not known. Here, we have investigated the effects of telomere shortening on adult neurogenesis and Alzheimer's disease progression in mice...
July 2011: Brain: a Journal of Neurology
Caroline C Rodgers
Despite the fact that Alzheimer's disease was identified more than 100 years ago, its cause remains elusive. Although the chance of developing Alzheimer's disease increases with age, it is not a natural consequence of aging. This article proposes that dental X-rays can damage microglia telomeres - the structures at the end of chromosomes that determine how many times cells divide before they die - causing them to age prematurely. Degenerated microglia lose their neuroprotective properties, resulting in the formation of neurofibrillary tau tangles and consequently, the neuronal death that causes Alzheimer's dementia...
July 2011: Medical Hypotheses
Anderson Hsien-Cheng Huang, Brooke R Snyder, Pei-Hsun Cheng, Anthony W S Chan
Until now, interest in dental pulp stem/stromal cell (DPSC) research has centered on mineralization and tooth repair. Beginning a new paradigm in DPSC research, we grafted undifferentiated, untreated DPSCs into the hippocampus of immune-suppressed mice. The rhesus DPSC (rDPSC) line used was established from the dental pulp of rhesus macaques and found to be similar to human bone marrow/mesenchymal stem cells, which express Nanog, Rex-1, Oct-4, and various cell surface antigens, and have multipotent differentiation capability...
October 2008: Stem Cells
Letizia Mazzini, Katia Mareschi, Ivana Ferrero, Elena Vassallo, Giuseppe Oliveri, Nicola Nasuelli, Gaia Donata Oggioni, Lucia Testa, Franca Fagioli
Amyotrophic Lateral Sclerosis is a progressive fatal neurodegenerative disease that targets motor neurons. Its origin is unknown but a main role of reactive astrogliosis and microglia activation in the pathogenesis has been recently demonstrated. Surrounding neurons with healthy adjoining cells completely stops motor neuron death in some cases. Hence stem cell transplantation might represent a promising therapeutic strategy. In this study MSCs were isolated from bone marrow of 9 patients with definite ALS. Growth kinetics, immunophenotype, telomere length and karyotype were evaluated during in vitro expansion...
February 15, 2008: Journal of the Neurological Sciences
Barry E Flanary, Nicole W Sammons, Cuong Nguyen, Douglas Walker, Wolfgang J Streit
Advanced age and presence of intracerebral amyloid deposits are known to be major risk factors for development of neurodegeneration in Alzheimer's disease (AD), and both have been associated with microglial activation. However, the specific role of activated microglia in AD pathogenesis remains unresolved. Here we report that microglial cells exhibit significant telomere shortening and reduction of telomerase activity with normal aging in rats, and that in humans there is a tendency toward telomere shortening with presence of dementia...
March 2007: Rejuvenation Research
Barry E Flanary, Wolfgang J Streit
Microglial cells undergo cell division in vitro, as well as in vivo after brain injury. Mitotic activity of microglia suggests that they have limited life spans and rely on self-renewal to replace senescent cells. In the current study we examined long-term effects of antioxidants vitamin E and alpha-lipoic acid on cultured rat microglia with respect to proliferative ability, telomere length, telomerase activity, and interleukin-1beta (IL-1beta) production. We report that vitamin E induces dramatic microglial proliferation, as measured by MTT assay and BrdU incorporation, surpassing that of the well-known microglial mitogen granulocyte macrophage-colony stimulating factor, and therefore establishing vitamin E as the most potent, known mitogen for microglia in vitro...
April 15, 2006: Glia
Barry E Flanary, Wolfgang J Streit
The adult central nervous system (CNS) is generally thought of as a postmitotic organ. However, DNA labeling studies have shown that one major population of nonneuronal cells, called microglia, retain significant mitotic potential. Microglial cell division is prominent during acute CNS injury involving neuronal damage or death. Prior work from this laboratory has shown that purified microglia maintained in vitro with continual mitogenic stimulation exhibit telomere shortening before entering senescence. In the current study, we sought to investigate whether telomere shortening occurs in dividing microglia in vivo...
October 15, 2005: Journal of Neuroscience Research
Barry Flanary
With each cell division, telomeres progressively shorten until they reach a critical length, at which point the cells enter cellular senescence. Microglia, a non-neuronal cell type residing within the central nervous system (CNS), play vital roles in maintaining neuronal function, health, and survival in both the normal and pathological CNS. A recent article described an increased incidence of microglial cytoplasmic structural abnormalities (i.e., swelling, twisted and shortened processes, and fragmentation) and dystrophy occurring in the cerebral cortex of human brains with age...
2005: Rejuvenation Research
Barry E Flanary, Wolfgang J Streit
Normal somatic cells have a finite replicative capacity. With each cell division, telomeres, the ends of linear chromosomes, progressively shorten until they reach a critical length, at which point the cells enter replicative senescence. Some cells maintain their telomeres by the action of the telomerase enzyme. Glia, particularly microglia, are the only adult cell type in the central nervous system (CNS) that exhibit a significant mitotic potential, and are thus susceptible to telomere shortening. Previous research in our laboratory has found that telomeres shorten in rat microglia with increasing time in vitro...
2003: Journal of Anti-aging Medicine
Barry E Flanary, Wolfgang J Streit
Normal somatic cells have a finite replicative capacity. With each cell division, telomeres shorten progressively until they reach a critical length, at which point the cells enter replicative senescence. Some cells maintain their telomeres by the action of the telomerase enzyme. Glia, particularly microglia, are the only adult cell types in the central nervous system (CNS) that exhibit a significant mitotic potential, and are thus susceptible to telomere shortening. In this study, we show that telomere shortening accompanied by low to moderate telomerase activity, and ultimately senescence, occurs in rat microglia in vitro...
January 1, 2004: Glia
Maria K Storch, Robert Weissert, Andreas Steffer, Robert Birnbacher, Erik Wallström, Ingrid Dahlman, Claes Göran Ostensson, Christopher Linington, Tomas Olsson, Hans Lassmann
Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in rats is a chronic inflammatory demyelinating disease of the central nervous system (CNS) strongly mimicking multiple sclerosis (MS). We determined the involvement of macrophages and microglia in the lesions of MOG-EAE in relation to different major histocompatibility complex (MHC, RT1 in rat) haplotypes. We used intra-RT1 recombinant rat strains with recombinations between the RT1a and RT1u haplotypes on the disease permissive LEW non-MHC genome...
July 2002: Brain Pathology
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