Acta Neuropathologica

, Volume 137, Issue 3, pp 413–436 | Cite as

Frontal cortex and striatal cellular and molecular pathobiology in individuals with Down syndrome with and without dementia

  • Sylvia E. Perez
  • Jennifer C. Miguel
  • Bin He
  • Michael Malek-Ahmadi
  • Eric E. Abrahamson
  • Milos D. Ikonomovic
  • Ira Lott
  • Eric Doran
  • Melissa J. Alldred
  • Stephen D. Ginsberg
  • Elliott J. MufsonEmail author
Original Paper


Although, by age 40, individuals with Down syndrome (DS) develop amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer’s disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD −) is under-investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as Aβ and its precursor protein (APP) to frontal cortex (FC) and striatal tissue from DSD + to DSD − cases. Expression profiling of single pS422 labeled FC layer V and VI neurons was also determined using laser capture microdissection and custom-designed microarray analysis. Analysis revealed that cortical and striatal Aβ plaque burdens were similar in DSD + and DSD − cases. In both groups, most FC plaques were neuritic, while striatal plaques were diffuse. By contrast, FC AT8-positive NFTs and neuropil thread densities were significantly greater in DSD + compared to DSD −, while striatal NFT densities were similar between groups. FC pS422-positive and TauC3 NFT densities were significantly greater than Alz50-labeled NFTs in DSD + , but not DSD − cases. Putaminal, but not caudate pS422-positive NFT density, was significantly greater than TauC3-positive NFTs. In the FC, AT8 + pS422 + Alz50, TauC3 + pS422 + Alz50, pS422 + Alz50, and TauC3 + pS422 positive NFTs were more frequent in DSD + compared to DSD- cases. Single gene-array profiling of FC pS422 positive neurons revealed downregulation of 63 of a total of 864 transcripts related to Aβ/tau biology, glutamatergic, cholinergic, and monoaminergic metabolism, intracellular signaling, cell homeostasis, and cell death in DSD + compared DSD − cases. These observations suggest that abnormal tau aggregation plays a critical role in the development of dementia in DS.


Down syndrome Dementia Amyloid Tau Microarray Frontal cortex Striatum 



We gratefully acknowledge the contribution of Ms. L. Shao and Mr. M. Nadeem. This work was supported by the National Institute of Health (grants: P01 AG025204 and R01 AG052528 to M.D.I, R01 AG061566 to E.J.M., PPG AG014449 to E.J.M., S.D.G. and M.D.I, R01 AG043375 to S.D.G. and E.J.M., and P01 AG017617 to S.D.G.), Bright Focus Foundation (E.J.M.), and by the Arizona Alzheimer’s Consortium at Barrow Neurological Institute (S.E.P.).

Author contributions

Study concept and design: SEP and EJM. Acquisition of data: SEP, JM, EA, MM-A and BH. Analysis and interpretation of data: SEP and EJM. Drafting of the article: SEP and EJM. Critical revision of the article for important intellectual content: MDI, EA, IL, ED, SDG, and MJA. Facilitation of access to DS tissue: IL and ED. Study supervision: EJM.

Compliance with ethical standards

Ethical responsibilities

All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors declared that the manuscript has not been submitted to other journal for publication or has been published previously partly or in full. The authors report no conflict of interest.

Supplementary material

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Supplementary material 1 (DOCX 12 kb)
401_2019_1965_MOESM2_ESM.pdf (1.3 mb)
Supplementary material 2 (PDF 1308 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sylvia E. Perez
    • 1
    • 2
  • Jennifer C. Miguel
    • 1
  • Bin He
    • 1
  • Michael Malek-Ahmadi
    • 3
  • Eric E. Abrahamson
    • 4
    • 5
  • Milos D. Ikonomovic
    • 4
    • 5
  • Ira Lott
    • 6
  • Eric Doran
    • 6
  • Melissa J. Alldred
    • 7
    • 8
  • Stephen D. Ginsberg
    • 7
    • 8
    • 9
  • Elliott J. Mufson
    • 1
    Email author
  1. 1.Department of Neurobiology and NeurologyBarrow Neurological InstitutePhoenixUSA
  2. 2.School of Life Sciences, College of Liberal Arts and SciencesArizona State UniversityTempeUSA
  3. 3.Banner Alzheimer’s InstitutePhoenixUSA
  4. 4.Geriatric Research Education and Clinical CenterVA Pittsburgh Healthcare SystemPittsburghUSA
  5. 5.Departments of Neurology and PsychiatryUniversity of PittsburghPittsburghUSA
  6. 6.Departments of Pediatrics and NeurologyUniversity of CaliforniaIrvineUSA
  7. 7.Center for Dementia ResearchNathan Kline InstituteOrangeburgUSA
  8. 8.Departments of PsychiatryNYU Neuroscience Institute, NYU Langone Medical CenterNew YorkUSA
  9. 9.Departments of Neuroscience and PhysiologyThe NYU Neuroscience Institute, NYU Langone Medical CenterNew YorkUSA

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