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Neuroglial Expression of the MHCI Pathway and PirB Receptor Is Upregulated in the Hippocampus with Advanced Aging

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Abstract

The hippocampus undergoes changes with aging that impact neuronal function, such as synapse loss and altered neurotransmitter release. Nearly half of the aged population also develops deficits in spatial learning and memory. To identify age-related hippocampal changes that may contribute to cognitive decline, transcriptomic analysis of synaptosome preparations from adult (12 months) and aged (28 months) Fischer 344–Brown Norway rats assessed for spatial learning and memory was performed. Bioinformatic analysis identified the MHCI pathway as significantly upregulated with aging. Age-related increases in mRNAs encoding the MHCI genes RT1-A1, RT1-A2, and RT1-A3 were confirmed by qPCR in synaptosomes and in CA1 and CA3 dissections. Elevated levels of the MHCI cofactor (B2m), antigen-loading components (Tap1, Tap2, Tapbp), and two known MHCI receptors (PirB, Klra2) were also confirmed. Protein expression of MHCI was elevated with aging in synaptosomes, CA1, and DG, while PirB protein expression was induced in both CA1 and DG. MHCI expression was localized to microglia and neuronal excitatory postsynaptic densities, and PirB was localized to neuronal somata, axons, and dendrites. Induction of the MHCI antigen processing and presentation pathway in hippocampal neurons and glia may contribute to age-related hippocampal dysfunction by increasing neuroimmune signaling or altering synaptic homeostasis.

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References

  • Atwal JK, Pinkston-Gosse J, Syken J (2008) PirB is a functional receptor for myelin inhibitors of axonal regeneration. Science 322:967–970

    Article  PubMed  CAS  Google Scholar 

  • Auer RN (1991) Excitotoxic mechanisms, and age-related susceptibility to brain damage in ischemia, hypoglycemia and toxic mussel poisoning. Neurotoxicology 12:541–546

    PubMed  CAS  Google Scholar 

  • Barnes CA (1979) Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 93:74–104

    Article  PubMed  CAS  Google Scholar 

  • Barnes CA (2003) Long-term potentiation and the ageing brain. Philos Trans R Soc Lond B Biol Sci 358:765–772

    Article  PubMed  CAS  Google Scholar 

  • Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I (2001) Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125:279–284

    Article  PubMed  CAS  Google Scholar 

  • Berchtold NC, Cribbs DH, Coleman PD et al (2008) Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc Natl Acad Sci USA 105:15605–15610

    Article  PubMed  CAS  Google Scholar 

  • Berlett BS, Stadtman ER (1997) Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 272:20313–20316

    Article  PubMed  CAS  Google Scholar 

  • Bjorkman PJ, Parham P (1990) Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem 59:253–288

    Article  PubMed  CAS  Google Scholar 

  • Blalock EM, Grondin R, Chen KC et al (2010) Aging-related gene expression in hippocampus proper compared with dentate gyrus is selectively associated with metabolic syndrome variables in rhesus monkeys. J Neurosci 30:6058–6071

    Article  PubMed  CAS  Google Scholar 

  • Boulanger LM (2009) Immune proteins in brain development and synaptic plasticity. Neuron 64:93–109

    Article  PubMed  CAS  Google Scholar 

  • Burke SN, Barnes CA (2006) Neural plasticity in the ageing brain. Nat Rev Neurosci 7:30–40

    Article  PubMed  CAS  Google Scholar 

  • Chicurel ME, Terrian DM, Potter H (1993) mRNA at the synapse: analysis of a synaptosomal preparation enriched in hippocampal dendritic spines. J Neurosci 13:4054–4063

    PubMed  CAS  Google Scholar 

  • Datwani A, McConnell MJ, Kanold PO et al (2009) Classical MHCI molecules regulate retinogeniculate refinement and limit ocular dominance plasticity. Neuron 64:463–470

    Article  PubMed  CAS  Google Scholar 

  • Edstrom E, Kullberg S, Ming Y, Zheng H, Ulfhake B (2004) MHC class I, beta2 microglobulin, and the INF-gamma receptor are upregulated in aged motoneurons. J Neurosci Res 78:892–900

    Article  PubMed  Google Scholar 

  • Fiocco AJ, Yaffe K (2010) Defining successful aging: the importance of including cognitive function over time. Arch Neurol 67:876–880

    Article  PubMed  Google Scholar 

  • Fourgeaud L, Boulanger LM (2010) Role of immune molecules in the establishment and plasticity of glutamatergic synapses. Eur J Neurosci 32:207–217

    Article  PubMed  Google Scholar 

  • Fourgeaud L, Davenport CM, Tyler CM, Cheng TT, Spencer MB, Boulanger LM (2010) MHC class I modulates NMDA receptor function and AMPA receptor trafficking. Proc Natl Acad Sci USA 107:22278–22283

    Article  PubMed  CAS  Google Scholar 

  • Gavilan MP, Revilla E, Pintado C et al (2007) Molecular and cellular characterization of the age-related neuroinflammatory processes occurring in normal rat hippocampus: potential relation with the loss of somatostatin GABAergic neurons. J Neurochem 103:984–996

    Article  PubMed  CAS  Google Scholar 

  • Geinisman Y, de Toledo-Morrell L, Morrell F (1986) Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats. Proc Natl Acad Sci USA 83:3027–3031

    Article  PubMed  CAS  Google Scholar 

  • Glynn MW, Elmer BM, Garay PA et al (2011) MHCI negatively regulates synapse density during the establishment of cortical connections. Nat Neurosci 14:442–451

    Article  PubMed  CAS  Google Scholar 

  • Goddard CA, Butts DA, Shatz CJ (2007) Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci USA 104:6828–6833

    Article  PubMed  Google Scholar 

  • Gylys KH, Fein JA, Cole GM (2000) Quantitative characterization of crude synaptosomal fraction (P-2) components by flow cytometry. J Neurosci Res 61:186–192

    Article  PubMed  CAS  Google Scholar 

  • Hara Y, Park CS, Janssen WG, Punsoni M, Rapp PR, Morrison JH (2011) Synaptic characteristics of dentate gyrus axonal boutons and their relationships with aging, menopause, and memory in female rhesus monkeys. J Neurosci 31:7737–7744

    Article  PubMed  CAS  Google Scholar 

  • Hedden T, Gabrieli JD (2004) Insights into the ageing mind: a view from cognitive neuroscience. Nat Rev Neurosci 5:87–96

    Article  PubMed  CAS  Google Scholar 

  • Huh GS, Boulanger LM, Du H, Riquelme PA, Brotz TM, Shatz CJ (2000) Functional requirement for class I MHC in CNS development and plasticity. Science 290:2155–2159

    Article  PubMed  CAS  Google Scholar 

  • Jarosinski KW, Massa PT (2002) Interferon regulatory factor-1 is required for interferon-gamma-induced MHC class I genes in astrocytes. J Neuroimmunol 122:74–84

    Article  PubMed  CAS  Google Scholar 

  • Kadish I, Thibault O, Blalock EM et al (2009) Hippocampal and cognitive aging across the lifespan: a bioenergetic shift precedes and increased cholesterol trafficking parallels memory impairment. J Neurosci 29:1805–1816

    Article  PubMed  CAS  Google Scholar 

  • Lanier LL (1998) NK cell receptors. Annu Rev Immunol 16:359–393

    Article  PubMed  CAS  Google Scholar 

  • Lavi E, Suzumura A, Murasko DM, Murray EM, Silberberg DH, Weiss SR (1988) Tumor necrosis factor induces expression of MHC class I antigens on mouse astrocytes. J Neuroimmunol 18:245–253

    Article  PubMed  CAS  Google Scholar 

  • Lawlor DA, Zemmour J, Ennis PD, Parham P (1990) Evolution of class-I MHC genes and proteins: from natural selection to thymic selection. Annu Rev Immunol 8:23–63

    Article  PubMed  CAS  Google Scholar 

  • Lein ES, Zhao X, Gage FH (2004) Defining a molecular atlas of the hippocampus using DNA microarrays and high-throughput in situ hybridization. J Neurosci 24:3879–3889

    Article  PubMed  CAS  Google Scholar 

  • Llorens F, Gil V, del Rio JA (2011) Emerging functions of myelin-associated proteins during development, neuronal plasticity, and neurodegeneration. FASEB J 25:463–475

    Article  PubMed  CAS  Google Scholar 

  • Long EO (1999) Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 17:875–904

    Article  PubMed  CAS  Google Scholar 

  • Long LH, Liu RL, Wang F et al (2009) Age-related synaptic changes in the CA1 stratum radiatum and spatial learning impairment in rats. Clin Exp Pharmacol Physiol 36:675–681

    Article  PubMed  CAS  Google Scholar 

  • Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64:110–122

    Article  PubMed  CAS  Google Scholar 

  • Massa PT, Ozato K, McFarlin DE (1993) Cell type-specific regulation of major histocompatibility complex (MHC) class I gene expression in astrocytes, oligodendrocytes, and neurons. Glia 8:201–207

    Article  PubMed  CAS  Google Scholar 

  • McConnell MJ, Huang YH, Datwani A, Shatz CJ (2009) H2-K(b) and H2-D(b) regulate cerebellar long-term depression and limit motor learning. Proc Natl Acad Sci USA 106:6784–6789

    Article  PubMed  CAS  Google Scholar 

  • Narum SR (2006) Beyond Bonferroni: less conservative analyses for conservation genetics. Conservation Genetics 7:783–787

    Article  CAS  Google Scholar 

  • Needleman LA, Liu XB, El-Sabeawy F, Jones EG, McAllister AK (2010) MHC class I molecules are present both pre- and postsynaptically in the visual cortex during postnatal development and in adulthood. Proc Natl Acad Sci USA 107:16999–17004

    Article  PubMed  CAS  Google Scholar 

  • Norris CM, Korol DL, Foster TC (1996) Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging. J Neurosci 16:5382–5392

    PubMed  CAS  Google Scholar 

  • Ogura K, Ogawa M, Yoshida M (1994) Effects of ageing on microglia in the normal rat brain: immunohistochemical observations. Neuroreport 5:1224–1226

    Article  PubMed  CAS  Google Scholar 

  • Ownby RL (2010) Neuroinflammation and cognitive aging. Curr Psychiatry Rep 12:39–45

    Article  PubMed  Google Scholar 

  • Paolicelli RC, Bolasco G, Pagani F et al (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458

    Article  PubMed  CAS  Google Scholar 

  • Radisky DC, Stallings-Mann M, Hirai Y, Bissell MJ (2009) Single proteins might have dual but related functions in intracellular and extracellular microenvironments. Nat Rev Mol Cell Biol 10:228–234

    Article  PubMed  CAS  Google Scholar 

  • Roumier A, Bechade C, Poncer JC et al (2004) Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse. J Neurosci 24:11421–11428

    Article  PubMed  CAS  Google Scholar 

  • Rowe WB, Blalock EM, Chen KC et al (2007) Hippocampal expression analyses reveal selective association of immediate-early, neuroenergetic, and myelinogenic pathways with cognitive impairment in aged rats. J Neurosci 27:3098–3110

    Article  PubMed  CAS  Google Scholar 

  • Rufer E, Leonhardt RM, Knittler MR (2007) Molecular architecture of the TAP-associated MHC class I peptide-loading complex. J Immunol 179:5717–5727

    PubMed  CAS  Google Scholar 

  • Shamy JL, Buonocore MH, Makaron LM, Amaral DG, Barnes CA, Rapp PR (2006) Hippocampal volume is preserved and fails to predict recognition memory impairment in aged rhesus monkeys (Macaca mulatta). Neurobiol Aging 27:405–1415

    Article  Google Scholar 

  • Shatz CJ (2009) MHC class I: an unexpected role in neuronal plasticity. Neuron 64:40–45

    Article  PubMed  CAS  Google Scholar 

  • Shi L, Linville MC, Tucker W, Sonntag WE, Brunso-Bechtold JK (2005) Differential effects of aging and insulin-like growth factor-1 on synapses in CA1 of rat hippocampus. Cereb Cortex 15:571–577

    Article  PubMed  Google Scholar 

  • Small GW (2002) What we need to know about age related memory loss. BMJ 324:1502–1505

    Article  PubMed  Google Scholar 

  • Sonntag WE, Bennett SA, Khan AS et al (2000) Age and insulin-like growth factor-1 modulate N-methyl-D-aspartate receptor subtype expression in rats. Brain Res Bull 51:331–338

    Article  PubMed  CAS  Google Scholar 

  • Streit WJ, Graeber MB, Kreutzberg GW (1989) Peripheral nerve lesion produces increased levels of major histocompatibility complex antigens in the central nervous system. J Neuroimmunol 21:117–123

    Article  PubMed  CAS  Google Scholar 

  • Syken J, Grandpre T, Kanold PO, Shatz CJ (2006) PirB restricts ocular-dominance plasticity in visual cortex. Science 313:1795–1800

    Article  PubMed  CAS  Google Scholar 

  • Takai T (2005) Paired immunoglobulin-like receptors and their MHC class I recognition. Immunology 115:433–440

    Article  PubMed  CAS  Google Scholar 

  • Tomaszewski FS, Cahn-Weiner DA, Harvey DJ et al (2009) Longitudinal changes in memory and executive functioning are associated with longitudinal change in instrumental activities of daily living in older adults. Clin Neuropsychol 23:446–461

    Article  Google Scholar 

  • VanGuilder HD, Bixler GV, Brucklacher RM et al (2011a) Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment. J Neuroinflammation 8:138

    Article  PubMed  CAS  Google Scholar 

  • VanGuilder HD, Bixler GV, Sonntag WE, Freeman WM (2012) Hippocampal expression of myelin-associated inhibitors is induced with age-related cognitive decline and correlates with deficits of spatial learning and memory. J Neurochem 121:77–98

    Article  PubMed  CAS  Google Scholar 

  • VanGuilder HD, Farley JA, Yan H et al (2011b) Hippocampal dysregulation of synaptic plasticity-associated proteins with age-related cognitive decline. Neurobiol Dis 43:201–212

    Article  PubMed  CAS  Google Scholar 

  • VanGuilder HD, Freeman WM (2011) The hippocampal neuroproteome with aging and cognitive decline: past progress and future directions. Front Aging Neurosci 3:8–21

    PubMed  CAS  Google Scholar 

  • VanGuilder HD, Yan H, Farley JA, Sonntag WE, Freeman WM (2010) Aging alters the expression of neurotransmission-regulating proteins in the hippocampal synaptoproteome. J Neurochem 113:1577–1588

    PubMed  CAS  Google Scholar 

  • Washburn LR, Zekzer D, Eitan S et al (2011) A potential role for shed soluble major histocompatibility class I molecules as modulators of neurite outgrowth. PLoS One 6:e18439

    Article  PubMed  CAS  Google Scholar 

  • Wu ZP, Washburn L, Bilousova TV et al (2011) Enhanced neuronal expression of major histocompatibility complex class I leads to aberrations in neurodevelopment and neurorepair. J Neuroimmunol 232:8–16

    Article  PubMed  CAS  Google Scholar 

  • Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25:181–213

    Article  PubMed  CAS  Google Scholar 

  • Zagrebelsky M, Schweigreiter R, Bandtlow CE, Schwab ME, Korte M (2010) Nogo-A stabilizes the architecture of hippocampal neurons. J Neurosci 30:13220–13234

    Article  PubMed  CAS  Google Scholar 

  • Zeier Z, Madorsky I, Xu Y, Ogle WO, Notterpek L, Foster TC (2011) Gene expression in the hippocampus: regionally specific effects of aging and caloric restriction. Mech Ageing Dev 132:8–19

    Article  PubMed  CAS  Google Scholar 

  • Zhai Y, Knechtle S (1998) Two distinct forms of soluble MHC class I molecules synthesized by different mechanisms in normal rat cells in vitro. Hum Immunol 59:404–414

    Article  PubMed  CAS  Google Scholar 

  • Zhong J, Zhang T, Bloch LM (2006) Dendritic mRNAs encode diversified functionalities in hippocampal pyramidal neurons. BMC Neurosci 7:17

    Article  PubMed  Google Scholar 

  • Zohar O, Reiter Y, Bennink JR et al (2008) Cutting edge: MHC class I–Ly49 interaction regulates neuronal function. J Immunol 180:6447–6451

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by funding from the National Institute on Aging, National Institutes of Health (5R01AG026607, 1F31AG038285), and Donald W. Reynolds Foundation. The authors wish to thank the Penn State College of Medicine Genome Sciences and Imaging Facilities and Robert Brucklacher for technical assistance and Wayne Jarvis for assistance with figure creation.

Conflict of interest

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Pharmacology, Penn State College of Medicine, 500 University Drive, R130, Hershey, PA, 17033, USA

    Heather D. VanGuilder Starkey, Colleen A. Van Kirk, Georgina V. Bixler, Caesar G. Imperio, Vijay P. Kale, Jacob M. Serfass & Willard M. Freeman

  2. Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Julie A. Farley, Han Yan, Junie P. Warrington, Song Han, Matthew Mitschelen & William E. Sonntag

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  1. Heather D. VanGuilder Starkey
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  2. Colleen A. Van Kirk
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Correspondence to Willard M. Freeman.

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Starkey, H.D.V., Van Kirk, C.A., Bixler, G.V. et al. Neuroglial Expression of the MHCI Pathway and PirB Receptor Is Upregulated in the Hippocampus with Advanced Aging. J Mol Neurosci 48, 111–126 (2012). https://doi.org/10.1007/s12031-012-9783-8

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