Sequence of Deposition of Heterogeneous Amyloid β-Peptides and APO E in Down Syndrome: Implications for Initial Events in Amyloid Plaque Formation
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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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APOE staining resembles the pattern of amyloid-β plaque pathology in DSAD and EOAD cases, with minimal staining in HA cases.
“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]
The ‘Temporal Sequence of Apo E Immunoreactivity’ section (page not specified) reports that Apo E plaque staining closely paralleled amyloid-β staining in Down syndrome cases. The Discussion (page not specified) also notes prior observations of Apo E in plaques in AD, but this paper does not establish the stated staining pattern specifically for EOAD or minimal staining in HA cases. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDifferences in amyloid-β plaques in DSAD that affect the sequestration of APOE may contribute to the differences in APOE abundance observed.
“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]
Down syndrome patients with trisomy-21 having an extra copy of APP develop typical Alzheimer's neuropathology including amyloid plaques and neurofibrillary tangles.
“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]
The earliest Aβ42 in plaques appears to be N-truncated.
“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]
N-terminal Aβ1-x/βCTF-specific antibodies fail to label N-truncated Aβ42 peptides that appear to be particularly important in AD.
“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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“…involved in Down’s syndrome, a condition that invariably develops the typical Alzheimer’s disease neuropathology by age 50, though they start developing amyloid plaques as early as age 12, long before they get neurofibrillary tangles and other Alzheimer’s disease lesions (Lemere et al. 1996).”
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“The strong correlation between NFTs and AD may be addressed by the fact that amyloid plaques are heterogenous (Kametani et al. 1994; Miller et al. 1993; Lemere et al. 1996) and do not account for total Ab levels in the brain.”
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“Moreover, the large number of activated microglia, reactive astrocytes, and dystrophic neurites, as markers of inflammation and potential sources of complement proteins, suggests that the cascade is active in the AD-type lesions that occur in DS. Apo J, a known inhibitor of C5b-9, showed much more IR than either C4d o…”
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- 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
- 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
- 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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