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Cited by 66Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDown syndrome and intellectual disability research

Distribution of microglial phenotypes as a function of age and Alzheimer's disease neuropathology in the brains of people with Down syndrome

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Martini, Alessandra C., Helman, Alex M., McCarty, Katie L., Lott, Ira T., Doran, Eric, Schmitt, Frederick A., Head, Elizabeth·2020·Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
DOI 10.1002/dad2.12113PMC PMC7560512
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Abstract

INTRODUCTION: Microglial cells play an important role in the development of Alzheimer's disease (AD). People with Down syndrome (DS) inevitably develop AD neuropathology (DSAD) by 40 years of age. We characterized the distribution of different microglial phenotypes in the brains of people with DS and DSAD. METHODS: Autopsy tissue from the posterior cingulate cortex (PCC) from people with DS, DSAD, and neurotypical controls was immunostained with the microglial marker Iba1 to assess five microglia morphological types. RESULTS: Individuals with DS have more hypertrophic microglial cells in their white matter. In the gray matter, individuals with DSAD had significantly fewer ramified microglia and more dystrophic microglia than controls and the younger individuals with DS. The DSAD group also exhibited more rod-shaped and amoeboid cells than the AD group. DISCUSSION: Individuals with DS and DSAD show a microglial phenotype that distinguishes them from non-DS controls.

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  1. [1]Rumble B, Retallack R, Hilbich C, Simms G, Multhaup G, Martins R, et al. Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. N Engl J Med. 1989; 320: 1446‐ 1452. 2566117
  2. [4]Prasher VP, Farrer MJ, Kessling AM, et al. Molecular mapping of Alzheimer‐type dementia in Down's syndrome. Ann Neurol. 1998; 43: 380‐ 383. 9506555
  3. [5]Schupf N, Zigman WB, Tang MX, et al. Change in plasma Ass peptides and onset of dementia in adults with Down syndrome. Neurology. 2010; 75: 1639‐ 1644. 21041786 PMC3385463
  4. [6]Schupf N, Lee A, Park N, et al. Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome. Neurobiol Aging. 2015; 36: 2907 e1‐10. PMC4562880 26166206
  5. [7]Dekker AD, Fortea J, Blesa R, De Deyn PP Cerebrospinal fluid biomarkers for Alzheimer's disease in Down syndrome. Alzheimers Dement (Amst). 2017; 8: 1‐ 10. 28413821 PMC5384293
  6. [8]Startin CM, Ashton NJ, Hamburg S, et al. Plasma biomarkers for amyloid, tau, and cytokines in Down syndrome and sporadic Alzheimer's disease. Alzheimers Res Ther. 2019; 11: 26. 30902060 PMC6429702
  7. [9]Fortea J, Carmona‐Iragui M, Benejam B, et al. Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with Down syndrome: a cross‐sectional study. Lancet Neurol. 2018; 17: 860‐ 869. 30172624
  8. [10]Ballard C, Mobley W, Hardy J, Williams G, Corbett A Dementia in Down's syndrome. Lancet Neurol. 2016; 15: 622‐ 636. 27302127
  9. [11]Sinai A, Mokrysz C, Bernal J, et al. Predictors of age of diagnosis and survival of Alzheimer's disease in Down syndrome. J Alzheimers Dis. 2018; 61: 717‐ 728. 29226868 PMC6004911
  10. [12]Schupf N, Sergievsky GH Genetic and host factors for dementia in Down's syndrome. Br J Psychiatry. 2002; 180: 405‐ 410. 11983636
  11. [13]Royston MC, McKenzie JE, Gentleman SM, et al. Overexpression of s100beta in Down's syndrome: correlation with patient age and with beta‐amyloid deposition. Neuropathol Appl Neurobiol. 1999; 25: 387‐ 393. 10564528
  12. [14]Griffin WS, Sheng JG, McKenzie JE, et al. Life‐long overexpression of S100beta in Down's syndrome: implications for Alzheimer pathogenesis. Neurobiol Aging. 1998; 19: 401‐ 405. 9880042 PMC3833593
  13. [15]Wilcock DM, Hurban J, Helman AM, et al. Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease. Neurobiol Aging. 2015; 36: 2468‐ 2474. 26103884 PMC4602365
  14. [16]Wilcock DM, Griffin WS Down's syndrome, neuroinflammation, and Alzheimer neuropathogenesis. J Neuroinflammation. 2013; 10: 84. 23866266 PMC3750399
  15. [17]Wilcock DM Neuroinflammation in the aging down syndrome brain; lessons from Alzheimer's disease. Curr Gerontol Geriatr Res. 2012; 2012: 170276. 22454637 PMC3290800
  16. [18]Perez SE, Miguel JC, He B, et al. Frontal cortex and striatal cellular and molecular pathobiology in individuals with Down syndrome with and without dementia. Acta Neuropathol. 2019; 137: 413‐ 436. 30734106 PMC6541490
  17. [21]Stoltzner SE, Grenfell TJ, Mori C, et al. Temporal accrual of complement proteins in amyloid plaques in Down's syndrome with Alzheimer's disease. Am J Pathol. 2000; 156: 489‐ 499. 10666378 PMC1850044
  18. [22]Naude PJ, Dekker AD, Coppus AM, et al. Serum NGAL is Associated with distinct plasma amyloid‐beta peptides according to the clinical diagnosis of dementia in Down syndrome. J Alzheimers Dis. 2015; 45: 733‐ 743. 25613101
  19. [23]Rodrigues R, Debom G, Soares F, et al. Alterations of ectonucleotidases and acetylcholinesterase activities in lymphocytes of Down syndrome subjects: relation with inflammatory parameters. Clin Chim Acta. 2014; 433: 105‐ 110. 24631131
  20. [27]Davies DS, Ma J, Jegathees T, Goldsbury C Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer's disease. Brain Pathol. 2017; 27: 795‐ 808. 27862631 PMC8029278
  21. [28]Torres‐Platas SG, Comeau S, Rachalski A, et al. Morphometric characterization of microglial phenotypes in human cerebral cortex. J Neuroinflammation. 2014; 11: 12. 24447857 PMC3906907
  22. [30]Griffin WS, Stanley LC, Ling C, et al. Brain interleukin 1 and S‐100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989; 86: 7611‐ 7615. 2529544 PMC298116
  23. [31]Xue QS, Streit WJ Microglial pathology in Down syndrome. Acta Neuropathol. 2011; 122: 455‐ 466. 21847625
  24. [32]Azari NP, Pettigrew KD, Pietrini P, Horwitz B, Schapiro MB Detection of an Alzheimer disease pattern of cerebral metabolism in Down syndrome. Dementia. 1994; 5: 69‐ 78. 8038869
  25. [33]Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol. 1997; 42: 85‐ 94. 9225689
  26. [34]Lin AL, Powell D, Caban‐Holt A, et al. (1)H‐MRS metabolites in adults with Down syndrome: effects of dementia. Neuroimage Clin. 2016; 11: 728‐ 735. 27330972 PMC4908308
  27. [37]Boche D, Perry VH, Nicoll JA Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol. 2013; 39: 3‐ 18. 23252647
  28. [38]Bachstetter AD, Van Eldik LJ, Schmitt FA, et al. Disease‐related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol Commun. 2015; 3: 32. 26001591 PMC4489160
  29. [39]Kettenmann H, Hanisch UK, Noda M, Verkhratsky A Physiology of microglia. Physiol Rev. 2011; 91: 461‐ 553. 21527731
  30. [40]Streit WJ, Xue QS, Tischer J, Bechmann I Microglial pathology. Acta Neuropathol Commun. 2014; 2: 142. 25257319 PMC4180960
  31. [42]Streit WJ, Sammons NW, Kuhns AJ, Sparks DL Dystrophic microglia in the aging human brain. Glia. 2004; 45: 208‐ 212. 14730714
  32. [43]Bachstetter AD, Norris CM, Sompol P, et al. Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age‐dependent progression of Alzheimer's disease‐related pathology. J Neurosci. 2012; 32: 10201‐ 10210. 22836255 PMC3419360
  33. [44]Bachstetter AD, Rowe RK, Kaneko M, Goulding D, Lifshitz J, Van Eldik LJ. The p38alpha MAPK regulates microglial responsiveness to diffuse traumatic brain injury. J Neurosci. 2013; 33: 6143‐ 6153. 23554495 PMC3667712
  34. [45]Paasila PJ, Davies DS, Kril JJ, Goldsbury C, Sutherland GT The relationship between the morphological subtypes of microglia and Alzheimer's disease neuropathology. Brain Pathol. 2019; 29: 726‐ 740. 30803086 PMC8028288
  35. [47]Bachstetter AD, Ighodaro ET, Hassoun Y, et al. Rod‐shaped microglia morphology is associated with aging in 2 human autopsy series. Neurobiol Aging. 2017; 52: 98‐ 105. 28131016 PMC5359029
  36. [48]Powell D, Caban‐Holt A, Jicha G, et al. Frontal white matter integrity in adults with Down syndrome with and without dementia. Neurobiol Aging. 2014; 35: 1562‐ 1569. 24582640 PMC3992921
  37. [50]Helman AM, Siever M, McCarty KL, et al. Microbleeds and cerebral amyloid angiopathy in the brains of people with Down syndrome with Alzheimer's disease. J Alzheimers Dis. 2019; 67: 103‐ 112. 30452414 PMC6424116
  38. [51]Wolf SA, Boddeke HW, Kettenmann H Microglia in Physiology and Disease. Annu Rev Physiol. 2017; 79: 619‐ 643. 27959620
  39. [52]Gefen T, Kim G, Bolbolan K, et al. Activated microglia in cortical white matter across cognitive aging trajectories. Front Aging Neurosci. 2019; 11: 94. 31139072 PMC6527736
  40. [54]Ohm DT, Kim G, Gefen T, et al. Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia. Neuropathol Appl Neurobiol. 2019; 45: 216‐ 229. 29679378 PMC6196127
  41. [55]Caso F, Agosta F, Mattavelli D, et al. White matter degeneration in atypical Alzheimer disease. Radiology. 2015; 277: 162‐ 172. 26018810
  42. [56]Head E, Azizeh BY, Lott IT, Tenner AJ, Cotman CW, Cribbs DH Complement association with neurons and beta‐amyloid deposition in the brains of aged individuals with Down syndrome. Neurobiol Dis. 2001; 8: 252‐ 265. 11300721
  43. [57]Ziebell JM, Taylor SE, Cao T, Harrison JL, Lifshitz J Rod microglia: elongation, alignment, and coupling to form trains across the somatosensory cortex after experimental diffuse brain injury. J Neuroinflammation. 2012; 9: 247. 23111107 PMC3526458
  44. [58]Streit WJ, Walter SA, Pennell NA Reactive microgliosis. Prog Neurobiol. 1999; 57: 563‐ 581. 10221782
  45. [60]Karperien A, Ahammer H, Jelinek HF Quantitating the subtleties of microglial morphology with fractal analysis. Front Cell Neurosci. 2013; 7: 3. 23386810 PMC3558688
  46. [61]Streit WJ, Braak H, Xue QS, Bechmann I Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol. 2009; 118: 475‐ 485. 19513731 PMC2737117
  47. [62]Auge E, Bechmann I, Llor N, Vilaplana J, Krueger M, Pelegri C Corpora amylacea in human hippocampal brain tissue are intracellular bodies that exhibit a homogeneous distribution of neo‐epitopes. Sci Rep. 2019; 9: 2063. 30765834 PMC6375970
  48. [63]Nishimura A, Sawada S, Ushiyama I, et al. Lectin‐histochemical detection of degenerative glycoconjugate deposits in human brain. Forensic Sci Int. 2000; 113: 265‐ 269. 10978635

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Authors
Martini, A. C., Helman, A. M., McCarty, K. L., Lott, I. T., Doran, E., Schmitt, F. A., & Head, E.
Affiliations
  • University of California, Irvine (US)
  • University of Kentucky (US)
Corresponding author
Head, Elizabeth
ORCID
Venue
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Publisher
Wiley
Published
2020-01
Volume
12
Issue
1
Pages
e12113-e12113
ISSN
2352-8729 (ISSN-L)
DOI
10.1002/dad2.12113
PMC
PMC7560512
OpenAlex
W3093375011
Cited by
66
References
15
Citations by year
2026: 4 · 2025: 11 · 2024: 13 · 2023: 9 · 2022: 14 · 2021: 14 · 2020: 1
FWCI
3.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
Funders
  • National Institute on Aging (P50AG016573, R01AG021912, U01AG051412, U19AG068054, P30AG066519)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD064993)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Keywords
microglial phenotype, Down syndrome, Alzheimer's disease pathology, microglial morphology, ramified microglia, Iba1, posterior cingulate cortex, age differences, white matter, gray matter

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