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01-12-2020 | Alzheimer's Disease | Review

HLA in Alzheimer’s Disease: Genetic Association and Possible Pathogenic Roles

Authors: Zi-Xuan Wang, Qi Wan, Ang Xing

Published in: NeuroMolecular Medicine | Issue 4/2020

Abstract

Alzheimer’s disease (AD) is commonly considered as the most prominent dementing disorder globally and is characterized by the deposition of misfolded amyloid-β (Aβ) peptide and the aggregation of neurofibrillary tangles. Immunological disturbances and neuroinflammation, which result from abnormal immunological reactivations, are believed to be the primary stimulating factors triggering AD-like neuropathy. It has been suggested by multiple previous studies that a bunch of AD key influencing factors might be attributed to genes encoding human leukocyte antigen (HLA), whose variety is an essential part of human adaptive immunity. A wide range of activities involved in immune responses may be determined by HLA genes, including inflammation mediated by the immune response, T-cell transendothelial migration, infection, brain development and plasticity in AD pathogenesis, and so on. The goal of this article is to review the recent epidemiological findings of HLA (mainly HLA class I and II) associated with AD and investigate to what extent the genetic variations of HLA were clinically significant as pathogenic factors for AD. Depending on the degree of contribution of HLA in AD pathogenesis, targeted research towards HLA may propel AD therapeutic strategies into a new era of development.

Adelson, J. D., et al. (2012). Neuroprotection from stroke in the absence of MHCI or PirB. Neuron, 73, 1100–1107. https://doi.org/10.1016/j.neuron.2012.01.020.CrossRefPubMedPubMedCentral

Aliseychik, M. P., Andreeva, T. V., & Rogaev, E. I. (2018). Immunogenetic factors of neurodegenerative diseases: The role of HLA class II. Biochemistry (Moscow), 83, 1104–1116. https://doi.org/10.1134/s0006297918090122.CrossRef

Borghese, F., & Clanchy, F. I. (2011). CD74: An emerging opportunity as a therapeutic target in cancer and autoimmune disease. Expert Opinion on Therapeutic Targets, 15, 237–251. https://doi.org/10.1517/14728222.2011.550879.CrossRefPubMed

Boulanger, L. M. (2009). Immune proteins in brain development and synaptic plasticity. Neuron, 64, 93–109. https://doi.org/10.1016/j.neuron.2009.09.001.CrossRefPubMed

Bullido, M. J., et al. (2007). A TAP2 genotype associated with Alzheimer's disease in APOE4 carriers. Neurobiology of Aging, 28, 519–523. https://doi.org/10.1016/j.neurobiolaging.2006.02.011.CrossRefPubMed

Busse, S., et al. (2015). Expression of HLA-DR, CD80, and CD86 in healthy aging and Alzheimer's disease. Journal of Alzheimer's Disease, 47, 177–184. https://doi.org/10.3233/JAD-150217.CrossRefPubMed

Bryan, K. J., et al. (2008). Expression of CD74 is increased in neurofibrillary tangles in Alzheimer's disease. Molecular Neurodegeneration, 3, 13. https://doi.org/10.1186/1750-1326-3-13.CrossRefPubMedPubMedCentral

Coe, H., & Michalak, M. (2010). ERp57, a multifunctional endoplasmic reticulum resident oxidoreductase. The International Journal of Biochemistry & Cell Biology, 42, 796–799. https://doi.org/10.1016/j.biocel.2010.01.009.CrossRef

Cuello, A. C., et al. (2010). Early-stage inflammation and experimental therapy in transgenic models of the Alzheimer-like amyloid pathology. Neurodegenerative Diseases, 7, 96–98. https://doi.org/10.1159/000285514.CrossRefPubMed

Davtyan, H., Ghochikyan, A., Petrushina, I., Hovakimyan, A., Davtyan, A., Cribbs, D. H., et al. (2014). The MultiTEP platform-based Alzheimer's disease epitope vaccine activates a broad repertoire of T helper cells in nonhuman primates. Alzheimers & Dementia, 10, 271–283. https://doi.org/10.1016/j.jalz.2013.12.003.CrossRef

Das, R., & Chinnathambi, S. (2019). Microglial priming of antigen presentation and adaptive stimulation in Alzheimer's disease. Cellular and Molecular Life Sciences, 76, 3681–3694. https://doi.org/10.1007/s00018-019-03132-2.CrossRefPubMed

De Re, V., Negi, S., Singh, H., & Mukhopadhyay, A. (2017). Gut bacterial peptides with autoimmunity potential as environmental trigger for late onset complex diseases: In–silico study. PLoS ONE, 12, e0180518. https://doi.org/10.1371/journal.pone.0180518.CrossRef

Elmer, B. M., & McAllister, A. K. (2012). Major histocompatibility complex class I proteins in brain development and plasticity. Trends in Neurosciences, 35, 660–670. https://doi.org/10.1016/j.tins.2012.08.001.CrossRefPubMedPubMedCentral

Erickson, R. R., et al. (2005). In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid. Biochemical and Biophysical Research Communications, 332, 50–57. https://doi.org/10.1016/j.bbrc.2005.04.090.CrossRefPubMed

Fiala, M., et al. (2005). Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer's disease patients. Journal of Alzheimer's Disease, 7, 221–232. discussion 255–262.CrossRef

Gate, D., et al. (2020). Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature, 577, 399–404. https://doi.org/10.1038/s41586-019-1895-7.CrossRefPubMedPubMedCentral

Giavarotti, L., et al. (2013). Mild systemic oxidative stress in the subclinical stage of Alzheimer's disease. Oxidative Medicine and Cellular Longevity, 2013, 609019. https://doi.org/10.1155/2013/609019.CrossRefPubMedPubMedCentral

Glynn, M. W., Elmer, B. M., Garay, P. A., Liu, X. B., Needleman, L. A., El-Sabeawy, F., et al. (2011). MHCI negatively regulates synapse density during the establishment of cortical connections. Nature Neuroscience, 14, 442–451. https://doi.org/10.1038/nn.2764.CrossRefPubMedPubMedCentral

Goddard, C. A., Butts, D. A., & Shatz, C. J. (2007). Regulation of CNS synapses by neuronal MHC class I. Proceedings of the National Academy of Sciences of the United States of America, 104, 6828–6833. https://doi.org/10.1073/pnas.0702023104.CrossRefPubMedPubMedCentral

Guerini, F. R., et al. (2009). HLA-A*01 is associated with late onset of Alzheimer's disease in Italian patients. International Journal of Immunopathology and Pharmacology, 22, 991–999. https://doi.org/10.1177/039463200902200414.CrossRefPubMed

Henschke, P. J., Bell, D. A., & Cape, R. D. (1978). Alzheimer's disease and HLA. Tissue Antigens, 12(2), 132–135.PubMed

Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015). Immune attack: The role of inflammation in Alzheimer disease. Nature Reviews Neuroscience, 16, 358–372. https://doi.org/10.1038/nrn3880.CrossRefPubMed

Hoozemans, J. J., Rozemuller, A. J., van Haastert, E. S., Eikelenboom, P., & van Gool, W. A. (2011). Neuroinflammation in Alzheimer's disease wanes with age. Journal of Neuroinflammation, 8, 171. https://doi.org/10.1186/1742-2094-8-171.CrossRefPubMedPubMedCentral

Huh, G. S., Boulanger, L. M., Du, H., Riquelme, P. A., Brotz, T. M., & Shatz, C. J. (2000). Functional requirement for class I MHC in CNS development and plasticity. Science, 290, 2155–2159.PubMedPubMedCentral

Ikeda, T., Yamamoto, K., Takahashi, K., Kaneyuki, H., & Yamada, M. (1991). Interleukin-2 receptor in peripheral blood lymphocytes of Alzheimer's disease patients. Acta Psychiatrica Scandinavica, 84, 262–265.PubMed

Itzhaki, R. F. (2018). Corroboration of a major role for herpes simplex virus type 1 in Alzheimer's disease. Frontiers in Aging Neuroscience, 10, 324. https://doi.org/10.3389/fnagi.2018.00324.CrossRefPubMedPubMedCentral

James, L. M., & Georgopoulos, A. P. (2019). Human leukocyte antigen as a key factor in preventing dementia and associated apolipoprotein E4 risk. Frontiers in Aging Neuroscience, 11, 82. https://doi.org/10.3389/fnagi.2019.00082.CrossRefPubMedPubMedCentral

Jiao, B., et al. (2015). Polygenic analysis of late-onset Alzheimer's disease from Mainland China. PLoS ONE, 10, e0144898. https://doi.org/10.1371/journal.pone.0144898.CrossRefPubMedPubMedCentral

Kessels, H. W., Nguyen, L. N., Nabavi, S., & Malinow, R. (2010). The prion protein as a receptor for amyloid-beta. Nature, 466, E3–4. https://doi.org/10.1038/nature09217. discussion E4–5.CrossRefPubMedPubMedCentral

Kim, T., et al. (2013). Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science, 341, 1399–1404. https://doi.org/10.1126/science.1242077.CrossRefPubMed

Kiyota, T., et al. (2015). AAV2/1 CD74 gene transfer reduces beta-amyloidosis and improves learning and memory in a mouse model of Alzheimer's disease. Molecular Therapy, 23, 1712–1721. https://doi.org/10.1038/mt.2015.142.CrossRefPubMedPubMedCentral

Kunkle, B. W., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., et al. (2019). Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nature Genetics, 51(3), 414–443. https://doi.org/10.1038/s41588-019-0358-2.CrossRefPubMedPubMedCentral

Kusdra, L., Rempel, H., Yaffe, K., & Pulliam, L. (2000). Elevation of CD69+ monocyte/macrophages in patients with Alzheimer's disease. Immunobiology, 202, 26–33. https://doi.org/10.1016/S0171-2985(00)80049-2.CrossRefPubMed

Lambert, J. C., et al. (2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nature Genetics, 45, 1452–1458. https://doi.org/10.1038/ng.2802.CrossRefPubMedPubMedCentral

Lauren, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., & Strittmatter, S. M. (2009). Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature, 457, 1128–1132. https://doi.org/10.1038/nature07761.CrossRefPubMedPubMedCentral

Lin, M., Zhao, L., Fan, J., Lian, X. G., Ye, J. X., Wu, L., et al. (2012). Association between HFE polymorphisms and susceptibility to Alzheimer's disease: A meta-analysis of 22 studies including 4,365 cases and 8,652 controls. Molecular Biology Reports, 39, 3089–3095. https://doi.org/10.1007/s11033-011-1072-z.CrossRefPubMed

Listi, F., et al. (2006). Association between the HLA-A2 allele and Alzheimer disease. Rejuvenation Research, 9, 99–101. https://doi.org/10.1089/rej.2006.9.99.CrossRefPubMed

Liu, Y. J., et al. (2010). Peripheral T cells derived from Alzheimer's disease patients overexpress CXCR2 contributing to its transendothelial migration, which is microglial TNF-alpha-dependent. Neurobiology of Aging, 31, 175–188. https://doi.org/10.1016/j.neurobiolaging.2008.03.024.CrossRefPubMed

Lu, R. C., et al. (2017). Association of HLA-DRB1 polymorphism with Alzheimer's disease: a replication and meta-analysis. Oncotarget, 8, 93219–93226. https://doi.org/10.18632/oncotarget.21479.CrossRefPubMedPubMedCentral

Lueg, G., et al. (2015). Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer's disease. Neurobiology of Aging, 36, 81–89. https://doi.org/10.1016/j.neurobiolaging.2014.08.008.CrossRefPubMed

Ma, S. L., Tang, N. L., Tam, C. W., Lui, V. W., Suen, E. W., Chiu, H. F., et al. (2008). Association between HLA-A alleles and Alzheimer's disease in a southern Chinese community. Dementia and Geriatric Cognitive Disorders, 26, 391–397. https://doi.org/10.1159/000164275.CrossRefPubMed

Mackenzie, I. R., & Munoz, D. G. (1998). Nonsteroidal anti-inflammatory drug use and Alzheimer-type pathology in aging. Neurology, 50, 986–990.CrossRef

Malm, T. M., Magga, J., Kuh, G. F., Vatanen, T., Koistinaho, M., & Koistinaho, J. (2008). Minocycline reduces engraftment and activation of bone marrow-derived cells but sustains their phagocytic activity in a mouse model of Alzheimer's disease. Glia, 56, 1767–1779. https://doi.org/10.1002/glia.20726.CrossRefPubMed

Man, S. M., et al. (2007). Peripheral T cells overexpress MIP-1alpha to enhance its transendothelial migration in Alzheimer's disease. Neurobiology of Aging, 28, 485–496. https://doi.org/10.1016/j.neurobiolaging.2006.02.013.CrossRefPubMed

Mansouri, L., et al. (2015). Association of HLA-DR/DQ polymorphism with Alzheimer's disease. American Journal of the Medical Sciences, 349, 334–337. https://doi.org/10.1097/MAJ.0000000000000416.CrossRefPubMed

Mathys, H., et al. (2019). Single-cell transcriptomic analysis of Alzheimer's disease. Nature, 570(7761), 332–337. https://doi.org/10.1038/s41586-019-1195-2.CrossRefPubMedPubMedCentral

Mawanda, F., & Wallace, R. (2013). Can infections cause Alzheimer's disease? Epidemiologic Reviews, 35, 161–180. https://doi.org/10.1093/epirev/mxs007.CrossRefPubMedPubMedCentral

McAllister, A. K. (2014). Major histocompatibility complex I in brain development and schizophrenia. Biological Psychiatry, 75, 262–268. https://doi.org/10.1016/j.biopsych.2013.10.003.CrossRefPubMed

McConnell, M. J., Huang, Y. H., Datwani, A., & Shatz, C. J. (2009). H2-K(b) and H2-D(b) regulate cerebellar long-term depression and limit motor learning. Proceedings of the National Academy of Sciences of the United States of America, 106, 6784–6789. https://doi.org/10.1073/pnas.0902018106.CrossRefPubMedPubMedCentral

McGeer, P. L., McGeer, E. G., & Yasojima, K. (2000). Alzheimer disease and neuroinflammation. Journal of Neural Transmission Supplementum, 59, 53–57.PubMed

Monsonego, A., et al. (2003). Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. Journal of Clinical Investigation, 112, 415–422. https://doi.org/10.1172/JCI18104.CrossRefPubMedPubMedCentral

Mori, Y., et al. (2008). Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast development. The Journal of Immunology, 181, 4742–4751.CrossRef

Needleman, L. A., Liu, X. B., El-Sabeawy, F., Jones, E. G., & McAllister, A. K. (2010). MHC class I molecules are present both pre- and postsynaptically in the visual cortex during postnatal development and in adulthood. Proceedings of the National Academy of Sciences of the United States of America, 107, 16999–17004. https://doi.org/10.1073/pnas.1006087107.CrossRefPubMedPubMedCentral

Neill, D., et al. (1999). Risk for Alzheimer's disease in older late-onset cases is associated with HLA-DRB1*03. Neuroscience Letters, 275, 137–140.CrossRef

O'Brien, T. A., Tiedemann, K., & Vowels, M. R. (2006). No longer a biological waste product: Umbilical cord blood. Medical Journal of Australia, 184, 407–410.CrossRef

Orgogozo, J. M., et al. (2003). Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology, 61, 46–54.CrossRef

Paloneva, J., et al. (2000). Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nature Genetics, 25, 357–361. https://doi.org/10.1038/77153.CrossRefPubMed

Parachikova, A., et al. (2007). Inflammatory changes parallel the early stages of Alzheimer disease. Neurobiology of Aging, 28, 1821–1833. https://doi.org/10.1016/j.neurobiolaging.2006.08.014.CrossRefPubMed

Rahim, M. M., et al. (2014). Ly49 receptors: Innate and adaptive immune paradigms. Frontiers in Immunology, 5, 145. https://doi.org/10.3389/fimmu.2014.00145.CrossRefPubMedPubMedCentral

Rana, P., et al. (2019). Evaluation of the common molecular basis in Alzheimer's and Parkinson's diseases. International Journal of Molecular Sciences, 20, 3730. https://doi.org/10.3390/ijms20153730.CrossRefPubMedCentral

Ribic, A., Flugge, G., Schlumbohm, C., Matz-Rensing, K., Walter, L., & Fuchs, E. (2011). Activity-dependent regulation of MHC class I expression in the developing primary visual cortex of the common marmoset monkey. Behavioral and Brain Functions, 7, 1. https://doi.org/10.1186/1744-9081-7-1.CrossRefPubMed

Saresella, M., et al. (2014). A complex proinflammatory role for peripheral monocytes in Alzheimer's disease. Journal of Alzheimer's Disease, 38, 403–413. https://doi.org/10.3233/JAD-131160.CrossRefPubMed

Schmitt, T. L., Steger, M. M., Pavelka, M., & Grubeck-Loebenstein, B. (1997). Interactions of the Alzheimer beta amyloid fragment (25–35) with peripheral blood dendritic cells. Mechanisms of Ageing and Development, 94, 223–232.PubMed

Steele, N. Z., et al. (2017). Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case-control study. PLoS Medicine, 14, e1002272. https://doi.org/10.1371/journal.pmed.1002272.CrossRefPubMedPubMedCentral

Su, H., Na, N., Zhang, X., & Zhao, Y. (2017). The biological function and significance of CD74 in immune diseases. Inflammation Research, 66, 209–216. https://doi.org/10.1007/s00011-016-0995-1.CrossRefPubMed

Tan, M. S., Jiang, T., Tan, L., & Yu, J. T. (2014). Genome-wide association studies in neurology. The Annals of Translational Medicine, 2, 124. https://doi.org/10.3978/j.issn.2305-5839.2014.11.12.CrossRefPubMed

Togo, T., et al. (2002). Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases. Journal of Neuroimmunology, 124, 83–92.PubMed

Trieb, K., Ransmayr, G., Sgonc, R., Lassmann, H., & Grubeck-Loebenstein, B. (1996). APP peptides stimulate lymphocyte proliferation in normals, but not in patients with Alzheimer's disease. Neurobiology of Aging, 17, 541–547.PubMed

Wang, Z. X., et al. (2017a). Effects of HLA-DRB1/DQB1 genetic variants on neuroimaging in healthy, mild cognitive impairment, and Alzheimer's disease cohorts. Molecular Neurobiology, 54, 3181–3188. https://doi.org/10.1007/s12035-016-9890-6.CrossRefPubMed

Wang, Z. X., et al. (2017b). HLA-A2 alleles mediate Alzheimer's disease by altering hippocampal volume. Molecular Neurobiology, 54, 2469–2476. https://doi.org/10.1007/s12035-016-9832-3.CrossRefPubMed

Washburn, L. R., et al. (2011). A potential role for shed soluble major histocompatibility class I molecules as modulators of neurite outgrowth. PLoS ONE, 6, e18439. https://doi.org/10.1371/journal.pone.0018439.CrossRefPubMedPubMedCentral

William, C. M., et al. (2012). Synaptic plasticity defect following visual deprivation in Alzheimer's disease model transgenic mice. Journal of Neuroscience, 32, 8004–8011. https://doi.org/10.1523/JNEUROSCI.5369-11.2012.CrossRefPubMed

Wojtera, M., Sobow, T., Kloszewska, I., Liberski, P. P., Brown, D. R., & Sikorska, B. (2012). Expression of immunohistochemical markers on microglia in Creutzfeldt-Jakob disease and Alzheimer's disease: Morphometric study and review of the literature. Folia Neuropathologica, 50, 74–84.PubMed

Wu, Z. P., et al. (2011). Enhanced neuronal expression of major histocompatibility complex class I leads to aberrations in neurodevelopment and neurorepair. Journal of Neuroimmunology, 232, 8–16. https://doi.org/10.1016/j.jneuroim.2010.09.009.CrossRefPubMed

Xia, M., Cheng, X., Yi, R., Gao, D., & Xiong, J. (2016). The binding receptors of abeta: An alternative therapeutic target for Alzheimer's disease. Molecular Neurobiology, 53, 455–471. https://doi.org/10.1007/s12035-014-8994-0.CrossRefPubMed

Xia, Z., et al. (2010). A putative Alzheimer's disease risk allele in PCK1 influences brain atrophy in multiple sclerosis. PLoS ONE, 5, e14169. https://doi.org/10.1371/journal.pone.0014169.CrossRefPubMedPubMedCentral

Xue, S. R., Xu, D. H., Yang, X. X., & Dong, W. L. (2009). Alterations in lymphocyte subset patterns and co-stimulatory molecules in patients with Alzheimer disease. Chinese Medical Journal (England), 122, 1469–1472.

Yang, Y. M., Shang, D. S., Zhao, W. D., Fang, W. G., & Chen, Y. H. (2013). Microglial TNF-alpha-dependent elevation of MHC class I expression on brain endothelium induced by amyloid-beta promotes T cell transendothelial migration. Neurochemical Research, 38, 2295–2304. https://doi.org/10.1007/s11064-013-1138-5.CrossRefPubMed

Zhan, X., Stamova, B., Jin, L. W., DeCarli, C., Phinney, B., & Sharp, F. R. (2016). Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology, 87, 2324–2332. https://doi.org/10.1212/WNL.0000000000003391.CrossRefPubMedPubMedCentral

Zhang, A., et al. (2013). The spatio-temporal expression of MHC class I molecules during human hippocampal formation development. Brain Research, 1529, 26–38. https://doi.org/10.1016/j.brainres.2013.07.001.CrossRefPubMed

Zota, V., et al. (2009). HLA-DR alleles in amyloid beta-peptide autoimmunity: A highly immunogenic role for the DRB1*1501 allele. Journal of Immunology, 183, 3522–3530. https://doi.org/10.4049/jimmunol.0900620.CrossRef

Title: HLA in Alzheimer’s Disease: Genetic Association and Possible Pathogenic Roles
Authors: Zi-Xuan Wang
Qi Wan
Ang Xing
Publication date: 01-12-2020
Publisher: Springer US
Keywords: Alzheimer's Disease
Alzheimer's Disease
Published in: NeuroMolecular Medicine / Issue 4/2020
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-020-08612-4

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HLA in Alzheimer’s Disease: Genetic Association and Possible Pathogenic Roles

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Keynote webinar | Spotlight on medication adherence

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