title: Menopause leads to elevated expression of macrophage-associated genes in the aging frontal cortex: rat and human studies identify strikingly similar changes.
abstract: BACKGROUND
  The intricate interactions between the immune, endocrine and central nervous systems shape the innate immune response of the brain. We have previously shown that estradiol suppresses expression of immune genes in the frontal cortex of middle-aged ovariectomized rats, but not in young ones reflecting elevated expression of these genes in middle-aged, ovarian hormone deficient animals. Here, we explored the impact of menopause on the microglia phenotype capitalizing on the differential expression of macrophage-associated genes in quiescent and activated microglia.
  
  
  METHODS
  We selected twenty-three genes encoding phagocytic and recognition receptors expressed primarily in microglia, and eleven proinflammatory genes and followed their expression in the rat frontal cortex by real-time PCR. We used young, middle-aged and middle-aged ovariectomized rats to reveal age- and ovariectomy-related alterations. We analyzed the expression of the same set of genes in the postcentral and superior frontal gyrus of pre- and postmenopausal women using raw microarray data from our previous study.
  
  
  RESULTS
  Ovariectomy caused up-regulation of four classic microglia reactivity marker genes including Cd11b, Cd18, Cd45 and Cd86. The change was reversible since estradiol attenuated transcriptional activation of the four marker genes. Expression of genes encoding phagocytic and toll-like receptors such as Cd11b, Cd18, C3, Cd32, Msr2 and Tlr4 increased, whereas scavenger receptor Cd36 decreased following ovariectomy. Ovarian hormone deprivation altered the expression of major components of estrogen and neuronal inhibitory signaling which are involved in the control of microglia reactivity. Strikingly similar changes took place in the postcentral and superior frontal gyrus of postmenopausal women.
  
  
  CONCLUSIONS
  Based on the overlapping results of rat and human studies we propose that the microglia phenotype shifts from the resting toward the reactive state which can be characterized by up-regulation of CD11b, CD14, CD18, CD45, CD74, CD86, TLR4, down-regulation of CD36 and unchanged CD40 expression. As a result of this shift, microglial cells have lower threshold for subsequent activation in the forebrain of postmenopausal women.
authors.affiliation: Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Szigony Utca 43, Budapest 1083, Hungary. sarvari@koki.hu
authors.forename: Miklós
authors.initials: M
authors.lastname: Sárvári
authors.forename: Erik
authors.initials: E
authors.lastname: Hrabovszky
authors.forename: Imre
authors.initials: I
authors.lastname: Kalló
authors.forename: Norbert
authors.initials: N
authors.lastname: Solymosi
authors.forename: István
authors.initials: I
authors.lastname: Likó
authors.forename: Nicole
authors.initials: N
authors.lastname: Berchtold
authors.forename: Carl
authors.initials: C
authors.lastname: Cotman
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Liposits
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008593:Menopause / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D010052:Ovariectomy; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D016207:Cytokines; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D006649:Histocompatibility Antigens; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C038353:histocompatibility antigens RT, rat; D004958:Estradiol