Article

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
ABSTRACT
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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    • "First, as neurons become damaged with age, there is a loss of inhibitory ligandreceptor interactions with microglia (Perry and Holmes, 2014 ). Second, misfolded proteins such as amyloid-b accumulate during normal ageing; amyloid-b has been found to elevate pro-inflammatory cytokines in microglia (Flanary et al., 2007; Perry and Holmes, 2014). Third, the increase of "
    [Show abstract] [Hide abstract] ABSTRACT: Ageing of the central nervous system results in a loss of both grey and white matter, leading to cognitive decline. Additional injury to both the grey and white matter is documented in many neurological disorders with ageing, including Alzheimer's disease, traumatic brain and spinal cord injury, stroke, and multiple sclerosis. Accompanying neuronal and glial damage is an inflammatory response consisting of activated macrophages and microglia, innate immune cells demonstrated to be both beneficial and detrimental in neurological repair. This article will propose the following: (i) infiltrating macrophages age differently from central nervous system-intrinsic microglia; (ii) several mechanisms underlie the differential ageing process of these two distinct cell types; and (iii) therapeutic strategies that selectively target these diverse mechanisms may rejuvenate macrophages and microglia for repair in the ageing central nervous system. Most responses of macrophages are diminished with senescence, but activated microglia increase their expression of pro-inflammatory cytokines while diminishing chemotactic and phagocytic activities. The senescence of macrophages and microglia has a negative impact on several neurological diseases, and the mechanisms underlying their age-dependent phenotypic changes vary from extrinsic microenvironmental changes to intrinsic changes in genomic integrity. We discuss the negative effects of age on neurological diseases, examine the response of senescent macrophages and microglia in these conditions, and propose a theoretical framework of therapeutic strategies that target the different mechanisms contributing to the ageing phenotype in these two distinct cell types. Rejuvenation of ageing macrophage/microglia may preserve neurological integrity and promote regeneration in the ageing central nervous system.
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    • "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). Reduced microglia replication could also result in a depletion of healthy microglia, favoring the participation of more senescent and dysfunctional cells (Mosher and Wyss-Coray, 2014). "
    [Show abstract] [Hide abstract] 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. "
    [Show abstract] [Hide abstract] 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.
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