title: Myeloid dendritic cells are decreased in peripheral blood of Alzheimer's disease patients in association with disease progression and severity of depressive symptoms.
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.
authors.affiliation: Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Experimental Neuro-psychobiology Lab, Via Ardeatina 306, 00179, Rome, Italy. a.ciaramella@hsantalucia.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ciaramella
authors.affiliation: Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Experimental Neuro-psychobiology Lab, Via Ardeatina 306, 00179, Rome, Italy. f.salani@hsantalucia.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Salani
authors.affiliation: Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Experimental Neuro-psychobiology Lab, Via Ardeatina 306, 00179, Rome, Italy. f.bizzoni@hsantalucia.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Bizzoni
authors.affiliation: Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Experimental Neuro-psychobiology Lab, Via Ardeatina 306, 00179, Rome, Italy. md.orfei@hsantalucia.it.
authors.forename: Maria Donata
authors.initials: MD
authors.lastname: Orfei
authors.affiliation: Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Experimental Neuro-psychobiology Lab, Via Ardeatina 306, 00179, Rome, Italy. c.caltagirone@hsantalucia.it.|Department of Neuroscience, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy. c.caltagirone@hsantalucia.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Caltagirone
authors.affiliation: Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Experimental Neuro-psychobiology Lab, Via Ardeatina 306, 00179, Rome, Italy. g.spalletta@hsantalucia.it.|Neuropsychology Unit, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy. g.spalletta@hsantalucia.it.|Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA. g.spalletta@hsantalucia.it.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Spalletta
authors.affiliation: Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Experimental Neuro-psychobiology Lab, Via Ardeatina 306, 00179, Rome, Italy. p.bossu@hsantalucia.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Bossù
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000150:complications* / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000209:etiology; D003713:Dendritic Cells / Q000473:pathology*; D003863:Depression / Q000209:etiology*; D018450:Disease Progression; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007558:Italy; D008297:Male; D022423:Myeloid Cells / Q000473:pathology*; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales
chemical_list: D006684:HLA-DR Antigens
references.citation: Brain Behav Immun. 2013 Aug;32:29-32
references.pmid: 23578995
references.citation: PLoS One. 2013;8(6):e65352
references.pmid: 23776473
references.citation: Diabetes. 2013 Jul;62(7):2481-91
references.pmid: 23396400
references.citation: Mult Scler. 2013 Jul;19(8):995-1002
references.pmid: 23369893
references.citation: J Exp Med. 2013 Jul 29;210(8):1635-46
references.pmid: 23835848
references.citation: Cell Rep. 2013 Nov 14;5(3):646-53
references.pmid: 24210819
references.citation: Cancer Res. 2014 Feb 1;74(3):705-15
references.pmid: 24366885
references.citation: PLoS One. 2014;9(2):e89216
references.pmid: 24586603
references.citation: Neurosci Lett. 2014 Mar 20;563:51-4
references.pmid: 24412678
references.citation: Mult Scler. 2014 Apr;20(5):548-57
references.pmid: 24057429
references.citation: Nat Rev Neurosci. 2014 May;15(5):300-12
references.pmid: 24713688
references.citation: Science. 2014 May 2;344(6183):519-23
references.pmid: 24786080
references.citation: J Immunol. 2014 Aug 1;193(3):1024-34
references.pmid: 24973447
references.citation: J Exp Med. 2014 Sep 22;211(10):1969-76
references.pmid: 25180061
references.citation: Exp Gerontol. 2015 May;65:8-15
references.pmid: 25752742
references.citation: Nature. 2015 Jul 16;523(7560):337-41
references.pmid: 26030524
references.citation: Nature. 2000 May 25;405(6785):458-62
references.pmid: 10839541
references.citation: Annu Rev Immunol. 2000;18:767-811
references.pmid: 10837075
references.citation: Neurobiol Aging. 2000 May-Jun;21(3):383-421
references.pmid: 10858586
references.citation: J Immunol. 2000 Dec 1;165(11):6037-46
references.pmid: 11086035
references.citation: Infect Immun. 2001 Aug;69(8):4703-8
references.pmid: 11447141
references.citation: Nat Rev Immunol. 2002 Mar;2(3):151-61
references.pmid: 11913066
references.citation: Brain Pathol. 2003 Jan;13(1):23-33
references.pmid: 12580542
references.citation: Immunol Lett. 2004 Mar 29;92(1-2):107-15
references.pmid: 15081534
references.citation: Mediators Inflamm. 2004 Jun;13(3):171-80
references.pmid: 15223608
references.citation: Gerontologist. 1969 Autumn;9(3):179-86
references.pmid: 5349366
references.citation: J Psychiatr Res. 1975 Nov;12(3):189-98
references.pmid: 1202204
references.citation: J Am Geriatr Soc. 1983 Dec;31(12):721-7
references.pmid: 6418786
references.citation: Neurosci Lett. 1994 Jun 20;174(2):130-2
references.pmid: 7970167
references.citation: Eur Neurol. 1996;36(6):378-84
references.pmid: 8954307
references.citation: Neurology. 1997 May;48(5 Suppl 6):S10-6
references.pmid: 9153155
references.citation: Int Psychogeriatr. 1997;9 Suppl 1:65-9
references.pmid: 9447429
references.citation: Gut. 2005 Feb;54(2):228-36
references.pmid: 15647187
references.citation: Neurobiol Dis. 2005 Feb;18(1):134-42
references.pmid: 15649704
references.citation: Annu Rev Immunol. 2005;23:275-306
references.pmid: 15771572
references.citation: J Alzheimers Dis. 2005 Jun;7(3):221-32; discussion 255-62
references.pmid: 16006665
references.citation: Exp Biol Med (Maywood). 2005 Nov;230(10):771-6
references.pmid: 16246905
references.citation: Neuropharmacology. 2006 Apr;50(5):540-7
references.pmid: 16336980
references.citation: Brain. 2006 May;129(Pt 5):1293-305
references.pmid: 16513684
references.citation: Clin Immunol. 2007 Feb;122(2):220-8
references.pmid: 17101294
references.citation: PLoS One. 2007;2(5):e458
references.pmid: 17520017
references.citation: Lancet Neurol. 2007 Aug;6(8):734-46
references.pmid: 17616482
references.citation: Eur J Neurosci. 2007 Jul;26(2):413-6
references.pmid: 17623022
references.citation: Exp Gerontol. 2007 Oct;42(10):1033-8
references.pmid: 17606348
references.citation: Neurobiol Aging. 2009 Feb;30(2):210-21
references.pmid: 17658667
references.citation: Clin Sci (Lond). 2010 Jan;118(2):147-57
references.pmid: 19508233
references.citation: Eur J Pharmacol. 2010 Jan 10;626(1):64-71
references.pmid: 19837057
references.citation: J Alzheimers Dis. 2010;19(2):559-72
references.pmid: 20110602
references.citation: J Exp Clin Cancer Res. 2010;29:78
references.pmid: 20565840
references.citation: Blood. 2010 Oct 21;116(16):e74-80
references.pmid: 20628149
references.citation: Biol Psychiatry. 2010 Nov 15;68(10):930-41
references.pmid: 20692646
references.citation: Cytometry B Clin Cytom. 2011 Jan;80(1):14-21
references.pmid: 20687203
references.citation: Alzheimers Dement. 2011 May;7(3):270-9
references.pmid: 21514249
references.citation: J Neuroimmunol. 2011 Jul;236(1-2):47-56
references.pmid: 21665296
references.citation: Blood. 2011 Jul 21;118(3):609-17
references.pmid: 21642595
references.citation: J Neurosci. 2011 Aug 3;31(31):11159-71
references.pmid: 21813677
references.citation: Mediators Inflamm. 2011;2011:941396
references.pmid: 21976788
references.citation: J Alzheimers Dis. 2012;30(3):685-710
references.pmid: 22466004
references.citation: Acta Neuropathol. 2012 Nov;124(5):599-614
references.pmid: 22825593
references.citation: J Neuroimmunol. 2013 Mar 15;256(1-2):38-42
references.pmid: 23380586