title: Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment.
abstract: BACKGROUND
  Age-related cognitive dysfunction, including impairment of hippocampus-dependent spatial learning and memory, affects approximately half of the aged population. Induction of a variety of neuroinflammatory measures has been reported with brain aging but the relationship between neuroinflammation and cognitive decline with non-neurodegenerative, normative aging remains largely unexplored. This study sought to comprehensively investigate expression of the MHC II immune response pathway and glial activation in the hippocampus in the context of both aging and age-related cognitive decline.
  
  
  METHODS
  Three independent cohorts of adult (12-13 months) and aged (26-28 months) F344xBN rats were behaviorally characterized by Morris water maze testing. Expression of MHC II pathway-associated genes identified by transcriptomic analysis as upregulated with advanced aging was quantified by qPCR in synaptosomal fractions derived from whole hippocampus and in hippocampal subregion dissections (CA1, CA3, and DG). Activation of astrocytes and microglia was assessed by GFAP and Iba1 protein expression, and by immunohistochemical visualization of GFAP and both CD74 (Ox6) and Iba1.
  
  
  RESULTS
  We report a marked age-related induction of neuroinflammatory signaling transcripts (i.e., MHC II components, toll-like receptors, complement, and downstream signaling factors) throughout the hippocampus in all aged rats regardless of cognitive status. Astrocyte and microglial activation was evident in CA1, CA3 and DG of intact and impaired aged rat groups, in the absence of differences in total numbers of GFAP+ astrocytes or Iba1+ microglia. Both mild and moderate microglial activation was significantly increased in all three hippocampal subregions in aged cognitively intact and cognitively impaired rats compared to adults. Neither induction of MHCII pathway gene expression nor glial activation correlated to cognitive performance.
  
  
  CONCLUSIONS
  These data demonstrate a novel, coordinated age-related induction of the MHC II immune response pathway and glial activation in the hippocampus, indicating an allostatic shift toward a para-inflammatory phenotype with advancing age. Our findings demonstrate that age-related induction of these aspects of hippocampal neuroinflammation, while a potential contributing factor, is not sufficient by itself to elicit impairment of spatial learning and memory in models of normative aging. Future efforts are needed to understand how neuroinflammation may act synergistically with cognitive-decline specific alterations to cause cognitive impairment.
authors: Department of Pharmacology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17057, USA.
authors: Heather D
authors: HD
authors: VanGuilder
authors: Georgina V
authors: GV
authors: Bixler
authors: Robert M
authors: RM
authors: Brucklacher
authors: Julie A
authors: JA
authors: Farley
authors: Han
authors: H
authors: Yan
authors: Junie P
authors: JP
authors: Warrington
authors: William E
authors: WE
authors: Sonntag
authors: Willard M
authors: WM
authors: Freeman
mesh_terms: D000375:Aging / Q000276:immunology / Q000502:physiology / Q000523:psychology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D003072:Cognition Disorders / Q000276:immunology* / Q000503:physiopathology; D020869:Gene Expression Profiling; D005802:Genes, MHC Class II; D006624:Hippocampus / Q000166:cytology* / Q000276:immunology* / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D008285:Major Histocompatibility Complex; D008297:Male; D018782:Maze Learning / Q000502:physiology; D046228:Microarray Analysis; D009457:Neuroglia / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D000949:Histocompatibility Antigens Class II