title: Astrocyte senescence as a component of Alzheimer's disease.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Rekha
authors.initials: R
authors.lastname: Bhat
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Crowe
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bitto
authors.forename: Michelle
authors.initials: M
authors.lastname: Moh
authors.forename: Christos D
authors.initials: CD
authors.lastname: Katsetos
authors.forename: Fernando U
authors.initials: FU
authors.lastname: Garcia
authors.forename: Frederick Bradley
authors.initials: FB
authors.lastname: Johnson
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Christian
authors.initials: C
authors.lastname: Sell
authors.forename: Claudio
authors.initials: C
authors.lastname: Torres
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D016466:CHO Cells; D002478:Cells, Cultured; D016922:Cellular Senescence; D006224:Cricetinae; D003412:Cricetulus; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015850:Interleukin-6; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1