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      Astrocyte Senescence as a Component of Alzheimer’s Disease


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          Aging is the main risk factor for Alzheimer’s disease (AD); however, the aspects of the aging process that predispose the brain to the development of AD are largely unknown. Astrocytes perform a myriad of functions in the central nervous system to maintain homeostasis and support neuronal function. In vitro, human astrocytes are highly sensitive to oxidative stress and trigger a senescence program when faced with multiple types of stress. In order to determine whether senescent astrocytes appear in vivo, brain tissue from aged individuals and patients with AD was examined for the presence of senescent astrocytes using p16 INK4a and matrix metalloproteinase-1 (MMP-1) expression as markers of senescence. Compared with fetal tissue samples ( n = 4), a significant increase in p16 INK4a-positive astrocytes was observed in subjects aged 35 to 50 years ( n = 6; P = 0.02) and 78 to 90 years ( n = 11; P<10 −6). In addition, the frontal cortex of AD patients ( n = 15) harbored a significantly greater burden of p16 INK4a-positive astrocytes compared with non-AD adult control subjects of similar ages ( n = 25; P = 0.02) and fetal controls ( n = 4; P<10 −7). Consistent with the senescent nature of the p16 INK4a-positive astrocytes, increased metalloproteinase MMP-1 correlated with p16 INK4a. In vitro, beta-amyloid 1–42 (Aβ 1–42) triggered senescence, driving the expression of p16 INK4a and senescence-associated beta-galactosidase. In addition, we found that senescent astrocytes produce a number of inflammatory cytokines including interleukin-6 (IL-6), which seems to be regulated by p38MAPK. We propose that an accumulation of p16 INK4a-positive senescent astrocytes may link increased age and increased risk for sporadic AD.

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          p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype.

          Cellular senescence suppresses cancer by forcing potentially oncogenic cells into a permanent cell cycle arrest. Senescent cells also secrete growth factors, proteases, and inflammatory cytokines, termed the senescence-associated secretory phenotype (SASP). Much is known about pathways that regulate the senescence growth arrest, but far less is known about pathways that regulate the SASP. We previously showed that DNA damage response (DDR) signalling is essential, but not sufficient, for the SASP, which is restrained by p53. Here, we delineate another crucial SASP regulatory pathway and its relationship to the DDR and p53. We show that diverse senescence-inducing stimuli activate the stress-inducible kinase p38MAPK in normal human fibroblasts. p38MAPK inhibition markedly reduced the secretion of most SASP factors, constitutive p38MAPK activation was sufficient to induce an SASP, and p53 restrained p38MAPK activation. Further, p38MAPK regulated the SASP independently of the canonical DDR. Mechanistically, p38MAPK induced the SASP largely by increasing NF-κB transcriptional activity. These findings assign p38MAPK a novel role in SASP regulation--one that is necessary, sufficient, and independent of previously described pathways.
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            Alzheimer disease in the US population: prevalence estimates using the 2000 census.

            Current and future estimates of Alzheimer disease (AD) are essential for public health planning. To provide prevalence estimates of AD for the US population from 2000 through 2050. Alzheimer disease incidence estimates from a population-based, biracial, urban study, using a stratified random sampling design, were converted to prevalence estimates and applied to US Census Bureau estimates of US population growth. A geographically defined community of 3 adjacent neighborhoods in Chicago, Ill, applied to the US population. Alzheimer disease incidence was measured in 3838 persons free of AD at baseline; 835 persons were evaluated for disease incidence. Main Outcome Measure Current and future estimates of prevalence of clinically diagnosed AD in the US population. In 2000, there were 4.5 million persons with AD in the US population. By 2050, this number will increase by almost 3-fold, to 13.2 million. Owing to the rapid growth of the oldest age groups of the US population, the number who are 85 years and older will more than quadruple to 8.0 million. The number who are 75 to 84 years old will double to 4.8 million, while the number who are 65 to 74 years old will remain fairly constant at 0.3 to 0.5 million. The number of persons with AD in the US population will continue to increase unless new discoveries facilitate prevention of the disease.
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              In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis.

              Extensive research causally links amyloid-beta peptide (A beta) to Alzheimer's disease, although the pathologically relevant A beta conformation remains unclear. A beta spontaneously aggregates into the fibrils that deposit in senile plaques. However, recent in vivo and in vitro reports describe a potent biological activity for oligomeric assemblies of A beta. To consistently prepare in vitro oligomeric and fibrillar forms of A beta 1-42, a detailed knowledge of how solution parameters influence structure is required. This manuscript represents the first study using a single chemically and structurally homogeneous unaggregated starting material to demonstrate that the formation of oligomers, fibrils, and fibrillar aggregates is determined by time, concentration, temperature, pH, ionic strength, and A beta species. We recently reported that oligomers inhibit neuronal viability 10-fold more than fibrils and approximately 40-fold more than unaggregated peptide, with oligomeric A beta 1-42-induced neurotoxicity significant at 10 nm. In addition, we were able to differentiate by structure and neurotoxic activity wild-type A beta1-42 from isoforms containing familial mutations (Dahlgren, K. N., Manelli, A. M., Stine, W. B., Jr., Baker, L. K., Krafft, G. A., and LaDu, M. J. (2002) J. Biol. Chem. 277, 32046-32053). Understanding the biological role of specific A beta conformations may define the link between A beta and Alzheimer's disease, re-focusing therapeutic approaches by identifying the pernicious species of A beta ultimately responsible for the cognitive dysfunction that defines the disease.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                12 September 2012
                : 7
                : 9
                : e45069
                [1 ]Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
                [2 ]Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
                University of Nebraska Medical Center, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: CT CS RB EPC JQT FBJ. Performed the experiments: RB EPC AB MM. Analyzed the data: CT CS RB EPC JQT FBJ CK AB MM. Contributed reagents/materials/analysis tools: JQT FBJ FUG CK. Wrote the paper: CT RB EPC CS.

                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 20 March 2012
                : 14 August 2012
                Page count
                Pages: 10
                The study was supported by National Institutes of Health/National Institute on Aging grants AG022443 (CS) and AG022443-S1 (CT); the Resident Research Fellowship, Drexel University College of Medicine, awarded to RB; the Medical Student Summer Research Fellowship, Drexel University College of Medicine, awarded to MM; and the Aging Initiative Fellowship, Drexel University College of Medicine, awarded to AB. EPC was supported by funds from the Department of Pathology, Drexel University College of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Anatomy and Physiology
                Immune Physiology
                Developmental Biology
                Organism Development
                Molecular Cell Biology
                Signal Transduction
                Signaling Cascades
                Stress Signaling Cascade
                Cellular Stress Responses
                Cellular Neuroscience
                Anatomy and Physiology
                Cell Physiology
                Alzheimer Disease
                Neurodegenerative Diseases



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