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Sequence of Deposition of Heterogeneous Amyloid β-Peptides and APO E in Down Syndrome: Implications for Initial Events in Amyloid Plaque Formation
Open accessAbstract
Patients with trisomy 21 [Down syndrome (DS)] progressively develop amyloid beta-protein (A beta) deposits and then other features of Alzheimer's disease (AD), apparently due to increased gene dosage and thus expression of the beta-amyloid precursor protein. Because the neuropathological phenotype in older DS subjects closely resembles that of AD, the examination of DS brains of increasing age provides a unique model of the progression of AD. Here, we characterized the deposition of several A beta peptides and apolipoprotein E in formalin-fixed brain sections from 29 DS subjects between 3 and 73 years old. Amyloid plaque number and the percentage of cortical area they occupied were quantified by computerized image analysis. A beta ending at amino acid 42 (A beta 42) was the earliest form of A beta deposited in DS cortex. It was observed in 7 of 16 young (3-30 years) subjects, with the earliest deposition occurring at age 12. A beta ending at residue 40 (A beta 40) was not detected until approximately age 30, a time when degenerating neurites around A beta immunoreactive (IR) plaques were first observed, and the frequency of A beta 40 IR plaques then rose with age. Even in old (51-73 years) DS subjects, A beta 42 IR plaques were always more abundant than A beta 40 IR plaques. A beta peptides starting at aspartate 1 or pyroglutamate 3 were detected in small subsets of compacted, neuritic plaques beginning around age 30 and rose with age, the latter species always exceeding the former. Thus, the N-termini of the A beta 42 peptides abundantly deposited in very young DS subjects remain unknown. Apo E was detectable in a small subset of A beta 42 IR plaques beginning at age 12 and rose steadily with age; it clearly followed the deposition of A beta. Our analysis of very young DS brains suggests that amyloid plaque formation begins with A beta 42-ending peptides, and the number and percentage of cortical area of A beta 42 plaques increase very little with advancing age, while other heterogeneous A beta species and Apo E progressively accrue onto plaques containing A beta 42.
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“As previously reported [39], APOE staining resembles the pattern of amyloid-β plaque pathology in DSAD and EOAD cases, with minimal staining in HA cases (Supplementary Fig. 9).”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [39]
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“Consistent with the known sequestration of APOE within amyloid-β plaques [39], which we also observe in this study, the differences in amyloid-β plaques in DSAD that affect the sequestration of APOE may contribute to the differences in APOE abundance we observe.”
From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [39]
In the citing paper
“Down syndrome (DS) patients with trisomy-21 having extra copy of APP gene develop typical Alzheimer’s neuropathology including amyloid plaques and neurofibrillary tangles.35–37”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [37]
In the citing paper
“the earliest Aβ42 in plaques appears to be N-truncated [98].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [98]
In the citing paper
“N-terminal Aβ1-x/βCTF-specific antibodies also fail to label N-truncated Aβ42 peptides that appear to be particularly important in AD [60, 98, 157, 158, 206].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [98]
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“However, in contrast to sporadic AD, amyloid plaques and neurofibrillary tangles in DS can start developing as early as in the teen years [35].”
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“The earliest amyloid deposits seen in very young individuals, approximately 12 years old, with DS have a diffuse morphology, and although these diffuse ‘‘plaques’’ label readily with Ab42 antibodies, they show no reactivity with either antibodies to Ab40, or with antibodies specific to the N-terminal region of the Ab…”
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“that in the AD associated with Down’s syndrome (DS) and in the early onset, familial AD associated with gene mutations, Aβ overproduction and accumulation precede tau aggregation [1,2,5,6,14,21,28].”
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“Consistent with the known sequestration of APOE within amyloid-β plaques [39], which we also observe in this study, the differences in amyloid-β plaques in DSAD that affect the sequestration of APOE may contribute to the differences in APOE abundance we observe.”
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“In DS, enlarged endosomes are seen as early as 28 weeks of gestation in neurons [10], which precedes diffuse Aβ plaque deposition which appears at around 12 years of age, and is followed by mature Aβ plaques when the individuals are in their 30s [14].”
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“Individuals with DS are considered to be on the AD continuum since birth (Jack et al., 2024), with evidence of AD pathology developing at age 12 years (Lemere et al., 1996).”
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“In contrast to sporadic AD, however, amyloid plaques and neurofibrillary tangles in DS start developing in people as early as 12 years of age [9].”
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BackgroundA two-step biopolymer nucleation model shows a nonequilibrium critical point.
Taylor, A. I. P., Gahan, L., Chakrabarti, B., & Staniforth, R. A. (2019) · Journal of Chemical Physics · doi:10.1063/5.0009394 · Cited by 2
“Biopolymer nucleation intermediates are responsible for toxicity in a huge range of human diseases [16, 18, 71–74], and the nonequilibrium critical point predicted by our model may explain the extreme sensitivity of many polymerization disorders to small changes in self-assembly conditions [105–107].”
BackgroundA two-step biopolymer nucleation model shows a nonequilibrium critical point
Taylor, A. I. P., Gahan, L. D., Chakrabarti, B., et al. (2020) · White Rose Research Online (University of Leeds, The University of Sheffield, University of York) · Cited by 3
Establishing the Links Between Aβ Aggregation and Cytotoxicity In Vitro Using Biophysical Approaches
Jan, A., & Lashuel, H. A. (2012) · Methods in molecular biology · doi:10.1007/978-1-61779-551-0_16 · Cited by 3
Cerebral lactate metabolism and memory: Implications for Alzheimer's disease
Harris, R. A. (2017) · Scholarship@Western (Western University) · Cited by 3
Beckert, B., Acker‐Palmer, A., & Volknandt, W. (2018) · Biological Chemistry · doi:10.1515/hsz-2017-0238 · Cited by 3
Role of Post‐translational Chemical Modifications in Amyloid Fibril Formation
Nilsson, M. R. (2005) · doi:10.1002/9783527619344.ch5 · Cited by 3
Physiological factors could enhance amyloid-beta toxicity
Hunya, Á. G. (2013) · SZTE Repository of Dissertations (University of Szeged) · doi:10.14232/phd.1674 · Cited by 3
Chapter 4. Emerging themes in Alzheimer's disease research: Paradigm shift in drug discovery
Morgan, T. E., & Krafft, G. A. (2002) · Annual reports in medicinal chemistry · doi:10.1016/s0065-7743(02)37005-2 · Cited by 3
Gandy, S. (2004) · Human Pathology · doi:10.1016/j.humpath.2004.01.003 · Cited by 3
Air Pollution and Human Brain Pathology
Calder√≥n-GarciduenÀúas, L., & Reed, W. (2006) · Informa Healthcare eBooks · doi:10.1201/9781420003147.ch19 · Cited by 2
De ziekte van Alzheimer bij mensen met het syndroom van Down
Dekker, A. D., & Deyn, P. P. D. (2018) · Neuropraxis · doi:10.1007/s12474-018-0182-y · Cited by 3
Clinical trials for Alzheimer's disease in Down syndrome
Rafii, M. S. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-818845-3.00017-7 · Cited by 2
Valle‐Tamayo, N., Aranha, M. R., Pérez‐González, R., Serrano‐Requena, S., Videla, L., Barroeta, I., Benejam, B., Chiva‐Blanch, G., Jiménez, A., Busciglio, J. A., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70137 · Cited by 2
Self-citationThe tale of donanemab: God is in the details
Saido, T. C., & Iwata, N. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251371240 · Cited by 2
“26 The resistance of plaque-associated peptides isolated from AD brains in the earlier days to Edman degradation 27 further supports their presence as major pathological forms.”
Self-citationSalari, S., & Bagheri, M. (2016) · Research Repository Portal (Ilam University of Medical Sciences) · Cited by 4
Nerve Growth Factor Compromise in Down Syndrome
Carmo, S. D., Kannel, B., & Cuello, A. C. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.719507 · Cited by 2
“As early as childhood, a fraction of people with DS present diffuse Aβ plaques within their brain (Lemere et al., 1996; Leverenz and Raskind, 1998).”
BackgroundCraft, D., Wein, L. M., & Selkoe, D. J. (2005) · International series in management science/operations research/International series in operations research & management science · doi:10.1007/1-4020-8066-2_32 · Cited by 3
Self-citationPerry, J. C., & Vann, S. D. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.08.004 · Cited by 2
“Diffuse A β plaques are comprised primarily of A β 42 and develop at a younger age, with the earliest cortical deposits being found in Down syndrome around age 12 (Lemere et al., 1996).”
BackgroundMetal Complexing Agents for the Treatment of Alzheimer's Disease
White, A. R., & Bush, A. I. (2007) · Springer eBooks · doi:10.1007/7355_2007_011 · Cited by 2
Immunohistochemical Analysis of Amyloid β-Protein Isoforms in CAA
Yamaguchi, H., & Maat–Schieman, M. L. C. (2000) · Springer eBooks · doi:10.1007/978-94-017-1007-7_10 · Cited by 2
Self-citationAmyloid Beta Peptide and the Amyloid Cascade Hypothesis
Abraham, C. R. (2011) · Wiley eBooks · doi:10.1002/9781444344110.ch8 · Cited by 2
Dual-mode cholinesterase inhibitors targeting muscarinic receptors
Elsinghorst, P. W. (2007) · bonndoc (University of Bonn) · Cited by 2
Mayeux, R. P., & Gandy, S. (2000) · Elsevier eBooks · doi:10.1016/b978-012288145-9/50112-1 · Cited by 3
The Cholinergic Neuronal Phenotype in Alzheimer's Disease
Blusztajn, J. K., & Berse, B. (2000) · Metabolic Brain Disease · doi:10.1023/a:1011161718572 · Cited by 2
Self-citationGenetic Studies of Alzheimer's Disease
Blom, E. S. (2008) · KTH Publication Database DiVA (KTH Royal Institute of Technology) · Cited by 2
CAA in Transgenic Mouse Models of Alzheimer’s Disease
Cole, G. M., & Yang, F. (2000) · Springer eBooks · doi:10.1007/978-94-017-1007-7_18 · Cited by 2
The cholinotrophic system in Down syndrome
Mufson, E. J., & Perez, S. E. (2025) · Handbook of clinical neurology · doi:10.1016/b978-0-443-19088-9.00017-2 · Cited by 1
A myeloid trisomy 21-associated gene variant is protective from Alzheimer’s disease
Jin, M., Ma, Z., Dang, R., Zhang, H., Kim, R., Xue, H., Pascual, J. R., Yu, H., Papetti, A. V., Liú, Y., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02117-8 · Cited by 9
Metadata
- Authors
- Lemere, C. A., Blusztajn, J. K., Yamaguchi, H., Wisniewski, T., Saido, T. C., & Selkoe, D. J.
- Affiliations
- Boston University (US)
- Gunma University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Brigham and Women's Hospital (US)
- Corresponding author
- Selkoe, D.J.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 1996-02
- Volume
- 3
- Issue
- 1
- Pages
- 16-32
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W1985323612
- Cited by
- 584
- References
- 0
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 24 · 2023: 12 · 2022: 17 · 2021: 27 · 2020: 20 · 2019: 18 · 2018: 18 · 2017: 18 · 2016: 17 · 2015: 21 · 2014: 22 · 2013: 15 · 2012: 17
- FWCI
- 14.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Foundation for Neurologic Diseases
- National Institutes of Health
- National Institute on Aging (AG 12749, AG-06173, R01AG012749)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Down syndrome, amyloid-beta, amyloid plaques, apolipoprotein E, amyloid-beta 42, Aβ40, neuritic plaques, Alzheimer's disease, amyloid precursor protein, cortical amyloid deposition
- MeSH terms
- Adolescent, Adult, Aged, Aging, Alzheimer Disease, Apolipoproteins E, Child, Child, Preschool, Down Syndrome, Female, Humans, Immunoenzyme Techniques, Male, Middle Aged, Nerve Tissue Proteins, Peptide Fragments, Staining and Labeling, Temporal Lobe, Amyloid beta-Peptides, Neurites, Amyloid beta-Protein Precursor, Neurofibrillary Tangles
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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