Evidence That Aging And Amyloid Promote Microglial Cell Senescence

Department of Neuroscience, University of Florida College of Medicine, McKnight Brain Institute, Gainesville, Florida 32610-0244, USA.
Rejuvenation Research (Impact Factor: 3.31). 04/2007; 10(1):61-74. DOI: 10.1089/rej.2006.9096
Source: PubMed


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. Human brains containing high amyloid loads demonstrate a significantly higher degree of microglial dystrophy than nondemented, amyloid-free control subjects. Collectively, these findings show that microglial cell senescence associated with telomere shortening and normal aging is exacerbated by the presence of amyloid. They suggest that degeneration of microglia is a factor in the pathogenesis of AD.

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    • "Microglia obtained from young mice have a small cell body and very long and slender ramifications . As mice age , microglia gradually show bigger cell bodies and progressively shorter and thicker cell processes . that aged microglia tend to show sustained responses ( Damani et al . , 2011 ) . Both in aging ( Flanary and Streit , 2004 ) and in AD ( Flanary et al . , 2007 ) , microglia show telomere shortening and decreased telomerase activity , which are speculated to be one of the factors underlying the diminution of some functional activities , such as clearance ( phagocytosis plus effective removal of the compounds ) and basal proliferation ( Harry , 2013 ) ."
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    ABSTRACT: Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergo phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of cytokines and an exacerbated inflammatory response to pathological changes. Whereas LPS increases nitric oxide secretion in microglia from young mice, induction of reactive oxygen species (ROS) predominates in older mice. Furthermore, there is accumulation of DNA oxidative damage in mitochondria of microglia during aging, and also an increased intracellular ROS production. Increased ROS activates the redox-sensitive nuclear factor kappa B, which promotes more neuroinflammation, and can be translated in functional deficits, such as cognitive impairment. Mitochondria-derived ROS and cathepsin B, are also necessary for the microglial cell production of interleukin-1β, a key inflammatory cytokine. Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists. Assessing this apparent contradiction, we have reported that TGFβ1 induction and activation of Smad3 signaling after inflammatory stimulation are reduced in adult mice. Other protective functions, such as phagocytosis, although observed in aged animals, become not inducible by inflammatory stimuli and TGFβ1. Here, we discuss data suggesting that mitochondrial and endolysosomal dysfunction could at least partially mediate age-associated microglial cell changes, and, together with the impairment of the TGFβ1-Smad3 pathway, could result in a reduction of protective activation and a facilitation of cytotoxic activation of microglia, resulting in the promotion of neurodegeneration.
    Full-text · Article · Aug 2015 · Frontiers in Aging Neuroscience
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    • "In accordance, a study analyzing telomere lengths in pure human microglia isolated from the brain shows significant shortening and predicted propensity for dementia (Flanary et al., 2007). Here, we show that microglia in G3 mTerc À/À mice display considerable telomere shortening compared to G1 mTerc À/À mice, analogous to results in aged human microglia (Flanary et al., 2007). On the other hand, microglia isolated from young (3 months) and aged (24 months) mice under healthy conditions do not show significant telomere shortening. "
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    ABSTRACT: 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). Late-generation mTerc−/− microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc−/− microglia are comparable with microglia derived from G1 mTerc−/− mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc−/− microglia mice show an enhanced pro-inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age-associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood–brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.
    Full-text · Article · Jul 2015 · Aging cell
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    • "A very recent study showed that telomerase is expressed in vitro in mouse neurons and microglia, and in the cytoplasm of mature human hippocampal neurons and activated microglia, but it is absent in astrocytes (Spilsbury et al., 2015) according to previous findings in mice (Fu et al., 2002; Flanary and Streit, 2005; Fu et al., 2000). Emerging evidences are showing that telomerase may play an important role in mammalian brain, even involved in AD pathological process (Franco et al., 2006; Flanary et al., 2007; Rolyan et al., 2011; Spilsbury et al., 2015). Zhu et al. (2000a,b); Zhu et al. (2000a,b) first reported that suppression of telomerase in embryonic mouse hippocampal neurons using antisense technology and telomerase inhibitor (3 -azido-2 ,3 -dideoxythymidine) significantly increases neurons vulnerability to cell death induced by A␤. "
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    ABSTRACT: The old age population is increasing worldwide as well as age related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD), which negatively impacts on the health care systems. Aging represents per se a risk factor for AD. Thus, the study and identification of pathways within the biology of aging represent an important end point for the development of novel and effective disease-modifying drugs to treat, delay, or prevent AD. Cellular senescence and telomere shortening represent suitable and promising targets. Several studies show that cellular senescence is tightly interconnected to aging and AD, while the role of telomere dynamic and stability in AD pathogenesis is still unclear. This review will focus on the linking mechanisms between cellular senescence, telomere shortening and AD. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Apr 2015 · Ageing Research Reviews
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