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Cited by 55Neuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanisms

Major Histocompatibility Complex class I proteins are critical for maintaining neuronal structural complexity in the aging brain

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Lazarczyk, Maciej J., Kemmler, Julia E., Eyford, Brett A., Short, Jennifer A., Varghese, Merina, Sowa, Allison, Dickstein, Daniel R., Yuk, Frank J. +5 more·2016·Scientific Reports
DOI 10.1038/srep26199PMC PMC4882527
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Abstract

Major histocompatibility complex class I (MHCI) proteins have been implicated in neuronal function through the modulation of neuritogenesis, synaptogenesis, synaptic plasticity and memory consolidation during development. However, the involvement of MHCI in the aged brain is unclear. Here we demonstrate that MHCI deficiency results in significant dendritic atrophy along with an increase in thin dendritic spines and a reduction in stubby spines in the hippocampus of aged (12 month old) mice. Ultrastructural analyses revealed a decrease in spine head diameter and post synaptic density (PSD) area, as well as an increase in overall synapse density and non-perforated, small spines. Interestingly, we found that the changes in synapse density and morphology appear relatively late (after the age of 6 months). Finally, we found a significant age dependent increase in the levels of the glutamate receptor, GluN2B in aged MHCI knockout mice, with no change in GluA2/3, VGluT1, PSD95 or synaptophysin. These results indicate that MHCI may be also be involved in maintaining brain integrity at post-developmental stages notably in the modulation of neuronal and spine morphology and synaptic function during non-pathological aging which could have significant implications for cognitive function.

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  • Aging enhances the expression of MHC class I molecules in the brain, leading to decreased cognitive function.

    “Furthermore, aging enhances the expression of MHC class I molecules in the brain; this leads to decreased cognitive function [8].”

    From Control of the temporal development of Alzheimer’s disease pathology by the MR1/MAIT cell axis (2023) · cites this paper as [8]

    The Abstract reports increased MHCI expression in both cognitively intact and impaired aged rats. It also says expression was higher in cognitively intact oldest-old humans but lower in cognitively impaired ones, and suggests that an age-related increase may help preserve cognitive function—not cause its decline. (LLM, conf=0.88)

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Research works printed but not linked: 46

  1. Joly E., Mucke L. & Oldstone M. B. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science 253, 1283– 1285 (1991). 1891717
  2. Lampson L. A. Interpreting MHC class I expression and class I/class II reciprocity in the CNS: reconciling divergent findings. Microsc Res Tech 32, 267– 285, doi: 10.1002/jemt.1070320402 (1995). 8573777 · DOI
  3. Rall G. F., Mucke L. & Oldstone M. B. Consequences of cytotoxic T lymphocyte interaction with major histocompatibility complex class I-expressing neurons in vivo. J Exp Med 182, 1201– 1212 (1995). 7595191 PMC2192211
  4. Miralves J.. High levels of MeCP2 depress MHC class I expression in neuronal cells. PLoS One 2, e1354, doi: 10.1371/journal.pone.0001354 (2007). 18159237 PMC2131781 · DOI
  5. Goddard C. A., Butts D. A. & Shatz C. J. Regulation of CNS synapses by neuronal MHC class I. Proc Natl Acad Sci USA 104, 6828– 6833, doi: 10.1073/pnas.0702023104 (2007). 17420446 PMC1871870 · DOI · Paper page
  6. Linda H., Hammarberg H., Piehl F., Khademi M. & Olsson T. Expression of MHC class I heavy chain and beta2-microglobulin in rat brainstem motoneurons and nigral dopaminergic neurons. J Neuroimmunol 101, 76– 86 (1999). 10580816
  7. Thams S., Oliveira A. & Cullheim S. MHC class I expression and synaptic plasticity after nerve lesion. Brain Res Rev 57, 265– 269, doi: 10.1016/j.brainresrev.2007.06.016 (2008). 17764750 · DOI
  8. Boulanger L. M. & Shatz C. J. Immune signalling in neural development, synaptic plasticity and disease. Nat Rev Neurosci 5, 521– 531, doi: 10.1038/nrn1428 (2004). 15208694 · DOI · Paper page
  9. Corriveau R. A., Huh G. S. & Shatz C. J. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21, 505– 520 (1998). 9768838
  10. Nelson P. A.. MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression. Learn Mem 20, 505– 517, doi: 10.1101/lm.031351.113 (2013). 23959708 PMC3744042 · DOI · Paper page
  11. Oliveira A. L.. A role for MHC class I molecules in synaptic plasticity and regeneration of neurons after axotomy. Proc Natl Acad Sci USA 101, 17843– 17848, doi: 10.1073/pnas.0408154101 (2004). 15591351 PMC539738 · DOI
  12. Dickstein D. L.. Changes in the structural complexity of the aged brain. Aging Cell 6, 275– 284, doi: 10.1111/j.1474-9726.2007.00289.x (2007). 17465981 PMC2441530 · DOI · Paper page
  13. VanGuilder Starkey H. D.. Neuroglial expression of the MHCI pathway and PirB receptor is upregulated in the hippocampus with advanced aging. J Mol Neurosci 48, 111– 126, doi: 10.1007/s12031-012-9783-8 (2012). 22562814 PMC3414657 · DOI
  14. Katsel P., Tan W. & Haroutunian V. Gain in brain immunity in the oldest-old differentiates cognitively normal from demented individuals. PLoS One 4, e7642, doi: 10.1371/journal.pone.0007642 (2009). 19865478 PMC2764344 · DOI
  15. Guerini F. R.. HLA-A*01 is associated with late onset of Alzheimer’s disease in Italian patients. Int J Immunopathol Pharmacol 22, 991– 999 (2009). 20074462
  16. Ma S. L.. Association between HLA-A alleles and Alzheimer’s disease in a southern Chinese community. Dement Geriatr Cogn Disord 26, 391– 397, doi: 10.1159/000164275 (2008). 18936542 · DOI
  17. Zhao X.. The effects of aging on N-methyl-D-aspartate receptor subunits in the synaptic membrane and relationships to long-term spatial memory. Neuroscience 162, 933– 945, doi: 10.1016/j.neuroscience.2009.05.018 (2009). 19446010 PMC2769499 · DOI
  18. Zamzow D. R., Elias V., Shumaker M., Larson C. & Magnusson K. R. An increase in the association of GluN2B containing NMDA receptors with membrane scaffolding proteins was related to memory declines during aging. J Neurosci 33, 12300– 12305, doi: 10.1523/JNEUROSCI.0312-13.2013 (2013). 23884936 PMC3721840 · DOI
  19. Ljunggren H. G.. MHC class I expression and CD8+ T cell development in TAP1/beta 2-microglobulin double mutant mice. Int Immunol 7, 975– 984 (1995). 7577806
  20. Van Kaer L., Ashton-Rickardt P. G., Ploegh H. L. & Tonegawa S. TAP1 mutant mice are deficient in antigen presentation, surface class I molecules, and CD4-8+ T cells. Cell 71, 1205– 1214 (1992). 1473153
  21. Ljunggren H. G., Van Kaer L., Ashton-Rickardt P. G., Tonegawa S. & Ploegh H. L. Differential reactivity of residual CD8+ T lymphocytes in TAP1 and beta 2-microglobulin mutant mice. Eur J Immunol 25, 174– 178, doi: 10.1002/eji.1830250129 (1995). 7843229 · DOI
  22. Bilousova T.. Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization. J Neuroimmunol 247, 1– 8, doi: 10.1016/j.jneuroim.2012.03.008 (2012). 22503373 PMC5776040 · DOI
  23. Murthy V. N., Schikorski T., Stevens C. F. & Zhu Y. Inactivity produces increases in neurotransmitter release and synapse size. Neuron 32, 673– 682 (2001). 11719207
  24. Adelson J. D.. Developmental Sculpting of Intracortical Circuits by MHC Class I H2-Db and H2-Kb. Cereb Cortex 26, 1453– 1463, doi: 10.1093/cercor/bhu243 (2016). 25316337 PMC4785944 · DOI
  25. Laguna Goya R., Tyers P. & Barker R. A. Adult neurogenesis is unaffected by a functional knock-out of MHC class I in mice. Neuroreport 21, 349– 353, doi: 10.1097/WNR.0b013e3283377463 (2010). 20147861 · DOI
  26. Wu Z. P.. Enhanced neuronal expression of major histocompatibility complex class I leads to aberrations in neurodevelopment and neurorepair. J Neuroimmunol 232, 8– 16, doi: 10.1016/j.jneuroim.2010.09.009 (2011). 20950866 PMC5776042 · DOI
  27. Glynn M. W.. MHCI negatively regulates synapse density during the establishment of cortical connections. Nat Neurosci 14, 442– 451, doi: 10.1038/nn.2764 (2011). 21358642 PMC3251641 · DOI · Paper page
  28. Lee H.. Synapse elimination and learning rules co-regulated by MHC class I H2-Db. Nature 509, 195– 200, doi: 10.1038/nature13154 (2014). 24695230 PMC4016165 · DOI · Paper page
  29. Bruel-Jungerman E., Davis S. & Laroche S. Brain plasticity mechanisms and memory: a party of four. Neuroscientist 13, 492– 505, doi: 10.1177/1073858407302725 (2007). 17901258 · DOI
  30. Brigman J. L.. Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. J Neurosci 30, 4590– 4600, doi: 10.1523/JNEUROSCI.0640-10.2010 (2010). 20357110 PMC2869199 · DOI · Paper page
  31. Gambrill A. C. & Barria A. NMDA receptor subunit composition controls synaptogenesis and synapse stabilization. Proc Natl Acad Sci USA 108, 5855– 5860, doi: 10.1073/pnas.1012676108 (2011). 21427228 PMC3078406 · DOI
  32. Brim B. L.. Memory in aged mice is rescued by enhanced expression of the GluN2B subunit of the NMDA receptor. Behav Brain Res 238, 211– 226, doi: 10.1016/j.bbr.2012.10.026 (2013). 23103326 PMC3540206 · DOI
  33. Perarnau B.. Single H2Kb, H2Db and double H2KbDb knockout mice: peripheral CD8+ T cell repertoire and anti-lymphocytic choriomeningitis virus cytolytic responses. Eur J Immunol 29, 1243– 1252, doi: 10.1002/(SICI)1521-4141(199904)29:04<1243::AID-IMMU1243>3.0.CO;2-A (1999). 10229092 · DOI
  34. Zijlstra M.. Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature 344, 742– 746, doi: 10.1038/344742a0 (1990). 2139497 · DOI
  35. Steele J. W.. Early fear memory defects are associated with altered synaptic plasticity and molecular architecture in the TgCRND8 Alzheimer’s disease mouse model. J Comp Neurol 522, 2319– 2335, doi: 10.1002/cne.23536 (2014). 24415002 PMC4251468 · DOI
  36. Price K. A.. Altered synaptic structure in the hippocampus in a mouse model of Alzheimer’s disease with soluble amyloid-beta oligomers and no plaque pathology. Mol Neurodegener 9, 41, doi: 10.1186/1750-1326-9-41 (2014). 25312309 PMC4210526 · DOI
  37. Tyan S. H.. Amyloid precursor protein (APP) regulates synaptic structure and function. Mol Cell Neurosci 51, 43– 52, doi: 10.1016/j.mcn.2012.07.009 (2012). 22884903 PMC3538857 · DOI · Paper page
  38. Sholl D. A. Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 87, 387– 406 (1953). 13117757 PMC1244622
  39. Rodriguez A., Ehlenberger D. B., Hof P. R. & Wearne S. L. Rayburst sampling, an algorithm for automated three-dimensional shape analysis from laser scanning microscopy images. Nat Protoc 1, 2152– 2161, doi: 10.1038/nprot.2006.313 (2006). 17487207 · DOI
  40. Rodriguez A., Ehlenberger D. B., Dickstein D. L., Hof P. R. & Wearne S. L. Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS One 3, e1997, doi: 10.1371/journal.pone.0001997 (2008). 18431482 PMC2292261 · DOI
  41. Rodriguez A., Ehlenberger D. B., Hof P. R. & Wearne S. L. Three-dimensional neuron tracing by voxel scooping. J Neurosci Methods 184, 169– 175, doi: 10.1016/j.jneumeth.2009.07.021 (2009). 19632273 PMC2753723 · DOI
  42. Janssen W. G.. Cellular and synaptic distribution of NR2A and NR2B in macaque monkey and rat hippocampus as visualized with subunit-specific monoclonal antibodies. Exp Neurol 191 Suppl 1, S28– 44, doi: 10.1016/j.expneurol.2004.08.020 (2005). 15629759 · DOI
  43. Hara Y.. Synaptic characteristics of dentate gyrus axonal boutons and their relationships with aging, menopause, and memory in female rhesus monkeys. J Neurosci 31, 7737– 7744, doi: 10.1523/JNEUROSCI.0822-11.2011 (2011). 21613486 PMC3103072 · DOI
  44. Hara Y.. Synaptic correlates of memory and menopause in the hippocampal dentate gyrus in rhesus monkeys. Neurobiol Aging 33(421), e417– 428, doi: 10.1016/j.neurobiolaging.2010.09.014 (2012). PMC3031995 21030115 · DOI
  45. Beecroft R. P., Roditi I. & Pearson T. W. Identification and characterization of an acidic major surface glycoprotein from procyclic stage Trypanosoma congolense. Mol Biochem Parasitol 61, 285– 294 (1993). 7903427
  46. Dickstein D. L., Brautigam H., Stockton S. D. Jr., Schmeidler J. & Hof P. R. Changes in dendritic complexity and spine morphology in transgenic mice expressing human wild-type tau. Brain Struct Funct 214, 161– 179, doi: 10.1007/s00429-010-0245-1 (2010). 20213269 PMC3032082 · DOI

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Authors
Lazarczyk, M. J., Kemmler, J. E., Eyford, B. A., Short, J. A., Varghese, M., Sowa, A., Dickstein, D. R., Yuk, F. J., Puri, R., Biron, K. E., Leist, M., Jefferies, W. A., & Dickstein, D. L.
Affiliations
  • University of Geneva (CH)
  • University of Konstanz (DE)
  • University of British Columbia (CA)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Dickstein, Dara L.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-05-27
Volume
6
Issue
1
Pages
26199-26199
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep26199
PMC
PMC4882527
OpenAlex
W2401059417
Cited by
55
References
7
Citations by year
2026: 4 · 2025: 8 · 2024: 5 · 2023: 10 · 2022: 6 · 2021: 7 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 1
FWCI
1.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KOPS (University of Konstanz) (submittedVersion, cc-by)
Funders
  • Icahn School of Medicine at Mount Sinai
  • Universität Konstanz
  • Canadian Institutes of Health Research (86739_1, 77631_1)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
MHC class I, neuronal aging, dendritic spine morphology, dendritic atrophy, hippocampus, synaptic density, postsynaptic density, GluN2B, glutamate receptors, synaptic function, cognitive aging
MeSH terms
Aging, Animals, Hippocampus, Neurons, Histocompatibility Antigens Class I, Mice, Knockout, Mice

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