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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Myeloid dendritic cells are decreased in peripheral blood of Alzheimer’s disease patients in association with disease progression and severity of depressive symptoms

Authors: Antonio Ciaramella, Francesca Salani, Federica Bizzoni, Maria Donata Orfei, Carlo Caltagirone, Gianfranco Spalletta, Paola Bossù

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Dendritic cells (DCs) are major orchestrators of immune responses and inflammation. They are migratory cells, which may play a role in Alzheimer’s disease (AD), as suggested by prior in vitro studies. With the intent to investigate the clinical relevance of DC modifications in vivo, the present study was aimed to evaluate the levels of blood DCs in AD patients, in relation to the progression of the disease, the severity of its symptoms, and the treatment with acetylcholinesterase inhibitors (AChEIs), a class of drugs used to improve cognitive functioning in people with dementia.

Methods

The two main subpopulations of immature blood DCs, namely myeloid (mDCs) and plasmacytoid (pDCs) cells, were evaluated by flow cytometry analysis in 106 AD patients, in comparison with the same cells from 65 individuals with mild cognitive impairment (MCI) and 73 healthy control subjects (HC). The relationship between blood DC levels and symptom severity was also assessed in AD patients, and their blood DC frequency was considered both in the absence or presence of treatment with AChEIs.

Results

A significant depletion in blood mDCs was observed in AD patients, as compared to HC and MCI subjects. At variance, pDC levels were comparable among the three groups of subjects. The mDC decrease was evident only after the emergence of AD clinical symptoms, as confirmed by the follow-up analysis of a subgroup of MCI subjects who exhibited a significant decline in mDCs after their conversion to AD. Notably, the mDC decline was inversely correlated in AD patients with the frequency and severity of depressive symptoms. Eventually, the mDC depletion was not observable in patients treated with AChEIs.

Conclusions

Our results provide the first evidence that blood mDC levels are dysregulated in AD. This phenomenon appears mainly linked to AD progression, associated with stronger severity of AD-related symptoms, and influenced by AChEI treatment. Taken all together, these data suggest that blood mDCs may serve as a cell source to test disease-induced and treatment-related changes and support the innovative notion that DCs play a role in AD, as ultimate evidence of the immune system participation in disease progression.
Literature
1.
2.
Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry. 2010;68:930–41.CrossRefPubMed
3.
Ciaramella A, Bizzoni F, Salani F, Vanni D, Spalletta G, Sanarico N, et al. Increased pro-inflammatory response by dendritic cells from patients with Alzheimer’s disease. J Alzheimers Dis. 2010;19:559–72.PubMed
4.
Shalit F, Sredni B, Stern L, Kott E, Huberman M. Elevated interleukin-6 secretion levels by mononuclear cells of Alzheimer’s patients. Neurosci Lett. 1994;174:130–2.CrossRefPubMed
5.
Fiala M, Lin J, Ringman J, Kermani-Arab V, Tsao G, Patel A, et al. Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J Alzheimers Dis. 2005;7:221–32. discussion 255–262.PubMed
6.
Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014;15:300–12.CrossRefPubMed
7.
Butovsky O, Kunis G, Koronyo-Hamaoui M, Schwartz M. Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer’s disease model. Eur J Neurosci. 2007;26(2):413–6.CrossRefPubMed
8.
Malm TM, Koistinaho M, Pärepalo M, Vatanen T, Ooka A, Karlsson S, et al. Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol Dis. 2005;18:134–42.CrossRefPubMed
9.
Mildner A, Schlevogt B, Kierdorf K, Böttcher C, Erny D, Kummer MP, et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J Neurosci. 2011;31:11159–71.CrossRefPubMed
10.
Michaud JP, Bellavance MA, Préfontaine P, Rivest S. Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep. 2013;5:646–53.CrossRefPubMed
11.
12.
Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767–811.CrossRefPubMed
13.
Pashenkov M, Teleshova N, Link H. Inflammation in the central nervous system: the role for dendritic cells. Brain Pathol. 2003;13:23–33.CrossRefPubMed
14.
D’Agostino PM, Gottfried-Blackmore A, Anandasabapathy N, Bulloch K. Brain dendritic cells: biology and pathology. Acta Neuropathol. 2012;124:599–614.PubMedCentralCrossRefPubMed
15.
16.
Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116:e74–80.CrossRefPubMed
17.
Della Bella S, Bierti L, Presicce P, Arienti R, Valenti M, Saresella M, et al. Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin Immunol. 2007;122:220–8.CrossRefPubMed
18.
Perez-Cabezas B, Naranjo-Gomez M, Fernandez MA, Grifols JR, Pujol-Borrell R, Borras FE. Reduced numbers of plasmacytoid dendritic cells in aged blood donors. Exp Gerontol. 2007;42:1033–8.CrossRefPubMed
19.
Thewissen K, Nuyts AH, Deckx N, Van Wijmeersch B, Nagels G, D’hooghe M, et al. Circulating dendritic cells of multiple sclerosis patients are proinflammatory and their frequency is correlated with MS-associated genetic risk factors. Mult Scler. 2014;20:548–57.CrossRefPubMed
20.
Yilmaz A, Fuchs T, Dietel B, Altendorf R, Cicha I, Stumpf C, et al. Transient decrease in circulating dendritic cell precursors after acute stroke: potential recruitment into the brain. Clin Sci (Lond). 2010;118:147–57.CrossRef
21.
Ciaramella A, Salani F, Bizzoni F, Pontieri FE, Stefani A, Pierantozzi M, et al. Blood dendritic cell frequency declines in idiopathic Parkinson’s disease and is associated with motor symptom severity. PLoS One. 2013;8, e65352.PubMedCentralCrossRefPubMed
22.
Ciaramella A, Sanarico N, Bizzoni F, Moro ML, Salani F, Scapigliati G, et al. Amyloid beta peptide promotes differentiation of pro-inflammatory human myeloid dendritic cells. Neurobiol Aging. 2009;30:210–21.CrossRefPubMed
23.
Ciaramella A, Salani F, Bizzoni F, Orfei MD, Langella R, Angelucci F, et al. The stimulation of dendritic cells by amyloid beta 1-42 reduces BDNF production in Alzheimer’s disease patients. Brain Behav Immun. 2013;32:29–32.CrossRefPubMed
24.
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:270–9.PubMedCentralCrossRefPubMed
25.
Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734–46.CrossRefPubMed
26.
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.CrossRefPubMed
27.
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Kokmen E, Tangelos EG. Aging, memory, and mild cognitive impairment. Int Psychogeriatr. 1997;9 Suppl 1:65–9.CrossRefPubMed
28.
Carlesimo GA, Caltagirone C, Gainotti G. The Mental Deterioration Battery: normative data, diagnostic reliability and qualitative analyses of cognitive impairment. The Group for the Standardization of the Mental Deterioration Battery. Eur Neurol. 1996;36:378–84.CrossRefPubMed
29.
Cummings JL. The neuropsychiatric inventory: assessing psychopathology in dementia patients. Neurology. 1997;48:S10–6.CrossRefPubMed
30.
Katz S. Assessing self-maintenance: activities of daily living, mobility, and instrumental activities of daily living. J Am Geriatr Soc. 1983;31:721–7.CrossRefPubMed
31.
Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9:179–86.CrossRefPubMed
32.
Stasiolek M, Bayas A, Kruse N, Wieczarkowiecz A, Toyka KV, Gold R, et al. Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis. Brain. 2006;129:1293–305.CrossRefPubMed
33.
Baumgart DC, Metzke D, Schmitz J, Scheffold A, Sturm A, Wiedenmann B, et al. Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells. Gut. 2005;54:228–36.PubMedCentralCrossRefPubMed
34.
Galgani M, Nugnes R, Bruzzese D, Perna F, De Rosa V, Procaccini C, et al. Meta-immunological profiling of children with type 1 diabetes identifies new biomarkers to monitor disease progression. Diabetes. 2013;62:2481–91.PubMedCentralCrossRefPubMed
35.
Robak E, Smolewski P, Wozniacka A, Sysa-Jedrzejowska A, Robak T. Clinical significance of circulating dendritic cells in patients with systemic lupus erythematosus. Mediators Inflamm. 2004;13:171–80.PubMedCentralCrossRefPubMed
36.
37.
Ye F, Yu Y, Hu Y, Lu W, Xie X. Alterations of dendritic cell subsets in the peripheral circulation of patients with cervical carcinoma. J Exp Clin Cancer Res. 2010;29:78.PubMedCentralCrossRefPubMed
38.
Nuyts AH, Lee WP, Bashir-Dar R, Berneman ZN, Cools N. Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies? Mult Scler. 2013;19:995–1002.CrossRefPubMed
39.
Van Vre EA, Van Brussel I, Bosmans JM, Vrints CJ, Bult H. Dendritic cells in human atherosclerosis: from circulation to atherosclerotic plaques. Mediators Inflamm. 2011;2011:941396.PubMedCentralPubMed
40.
Pinzon-Charry A, Woodberry T, Kienzle V, McPhun V, Minigo G, Lampah DA, et al. Apoptosis and dysfunction of blood dendritic cells in patients with falciparum and vivax malaria. J Exp Med. 2013;210:1635–46.PubMedCentralCrossRefPubMed
41.
Meyers JH, Justement JS, Hallahan CW, Blair ET, Sun YA, O’Shea MA, et al. Impact of HIV on cell survival and antiviral activity of plasmacytoid dendritic cells. PLoS One. 2007;2, e458.PubMedCentralCrossRefPubMed
42.
Riccardi F, Della Porta MG, Rovati B, Casazza A, Radolovich D, De Amici M, et al. Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis. Cytometry B Clin Cytom. 2011;80:14–21.CrossRefPubMed
43.
Crossgrove JS, Li GJ, Zheng W. The choroid plexus removes beta-amyloid from brain cerebrospinal fluid. Exp Biol Med (Maywood). 2005;230:771–6.
44.
Karman J, Ling C, Sandor M, Fabry Z. Dendritic cells in the initiation of immune responses against central nervous system-derived antigens. Immunol Lett. 2004;92:107–15.CrossRefPubMed
45.
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015.
46.
Raj T, Rothamel K, Mostafavi S, Ye C, Lee MN, Replogle JM, et al. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science. 2014;344:519–23.CrossRefPubMed
47.
Hu N, Tan MS, Sun L, Jiang T, Wang YL, Tan L, et al. Decreased expression of CD33 in peripheral mononuclear cells of Alzheimer’s disease patients. Neurosci Lett. 2014;563:51–4.CrossRefPubMed
48.
Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005;23:275–306.CrossRefPubMed
49.
Caraci F, Copani A, Nicoletti F, Drago F. Depression and Alzheimer’s disease: neurobiological links and common pharmacological targets. Eur J Pharmacol. 2010;626:64–71.CrossRefPubMed
50.
Spalletta G, Caltagirone C, Padovani A, Sorbi S, Attar M, Colombo D, et al. Cognitive and affective changes in mild to moderate Alzheimer’s disease patients undergoing switch of cholinesterase inhibitors: a 6-month observational study. PLoS One. 2014;9, e89216.PubMedCentralCrossRefPubMed
51.
Nizri E, Hamra-Amitay Y, Sicsic C, Lavon I, Brenner T. Anti-inflammatory properties of cholinergic up-regulation: a new role for acetylcholinesterase inhibitors. Neuropharmacology. 2006;50:540–7.CrossRefPubMed
52.
Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62.CrossRefPubMed
53.
Salamone G, Lombardi G, Gori S, Nahmod K, Jancic C, Amaral MM, et al. Cholinergic modulation of dendritic cell function. J Neuroimmunol. 2011;236:47–56.CrossRefPubMed
54.
Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, et al. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol. 2000;165(11):6037–46.CrossRefPubMed
55.
Goc J, Germain C, Vo-Bourgais TK, Lupo A, Klein C, Knockaert S, et al. Dendritic cells in tumor-associated tertiary lymphoid structures signal a Th1 cytotoxic immune contexture and license the positive prognostic value of infiltrating CD8+ T cells. Cancer Res. 2014;74(3):705–15.CrossRefPubMed
56.
Defays A, David A, de Gassart A, De Angelis Rigotti F, Wenger T, Camossetto V, et al. BAD-LAMP is a novel biomarker of nonactivated human plasmacytoid dendritic cells. Blood. 2011;118(3):609–17.CrossRefPubMed
57.
Xia CQ, Peng R, Chernatynskaya AV, Yuan L, Carter C, Valentine J, et al. Increased IFN-α-producing plasmacytoid dendritic cells (pDCs) in human Th1-mediated type 1 diabetes: pDCs augment Th1 responses through IFN-α production. J Immunol. 2014;193(3):1024–34.PubMedCentralCrossRefPubMed
58.
Sisirak V, Ganguly D, Lewis KL, Couillault C, Tanaka L, Bolland S, et al. Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus. J Exp Med. 2014;211(10):1969–76.PubMedCentralCrossRefPubMed
59.
Lunnon K, Ibrahim Z, Proitsi P, Lourdusamy A, Newhouse S, Sattlecker M, et al. Mitochondrial dysfunction and immune activation are detectable in early Alzheimer’s disease blood. J Alzheimers Dis. 2012;30(3):685–710.PubMed
60.
Zhang R, Miller RG, Madison C, Jin X, Honrada R, Harris W, et al. Systemic immune system alterations in early stages of Alzheimer’s disease. J Neuroimmunol. 2013;256(1–2):38–42.PubMedCentralCrossRefPubMed
Metadata
Title
Myeloid dendritic cells are decreased in peripheral blood of Alzheimer’s disease patients in association with disease progression and severity of depressive symptoms
Authors
Antonio Ciaramella
Francesca Salani
Federica Bizzoni
Maria Donata Orfei
Carlo Caltagirone
Gianfranco Spalletta
Paola Bossù
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0483-0

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