Cited by 584Alzheimer's disease research and treatmentsDown syndrome and intellectual disability researchDementia and Cognitive Impairment Research

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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

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Lemere, C.A., Blusztajn, J.K., Yamaguchi, H., Wisniewski, T., Saido, T.C., Selkoe, D.J.·1996·Neurobiology of Disease

DOI 10.1006/nbdi.1996.0003

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Abstract

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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Buss, L., Fisher, E., Hardy, J., Nižetić, D., Groet, J., Pulford, L. J., & Strydom, A. (2016) · F1000Research · doi:10.12688/f1000research.7819.1 · Cited by 48
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The advent of Alzheimer treatments will change the trajectory of human aging
Selkoe, D. J. (2024) · Nature Aging · doi:10.1038/s43587-024-00611-5 · Cited by 49
“Here, the cause is a lifelong elevated dosage of wild-type APP 34 , producing classical AD neuropathology: diffuse Aβ deposits followed by microgliosis, astrocytosis and deposition of wild-type tau in surrounding dystrophic neurites and neurofibrillary tangles 35,36 .”
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Down syndrome, beta-amyloid and neuroimaging
Head, E., Helman, A. M., Powell, D. K., & Schmitt, F. A. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.09.013 · Cited by 49
Galanin Fiber Hypertrophy within the Cholinergic Nucleus Basalis during the Progression of Alzheimer’s Disease
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“The brains of subjects with Down’s syndrome are characterized by an age-related loss of CBF neurons and significant NB and cortical amyloid deposition. However, the majority of amyloid deposits in these patients are diffuse with less frequent senile plaques like those that predominate in the end-stage AD brain [”
Background
Neuropathological correlates of amyloid PET imaging in Down syndrome
Abrahamson, E. E., Head, E., Lott, I. T., Handen, B. L., Mufson, E. J., Christian, B. T., Klunk, W. E., & Ikonomović, M. D. (2019) · Developmental Neurobiology · doi:10.1002/dneu.22713 · Cited by 46
“, 2015), in agreement with postmortem neuropathology analyses (Davidson et al., 2018; Ikeda, Yanagisawa, et al., 1989; Lemere et al., 1996; Leverenz & Raskind, 1998; Mann, 1988a; Mann, Jones, et al., 1990; Mann et al., 1986; Motte & Williams, 1989).”
BackgroundResultInfluential
Chronic PERK induction promotes Alzheimer-like neuropathology in Down syndrome: Insights for therapeutic intervention
Lanzillotta, C., Zuliani, I., Tramutola, A., Barone, E., Blarzino, C., Folgiero, V., Caforio, M., Valentini, D., Villani, A., Locatelli, F., et al. (2020) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2020.101892 · Cited by 46
Following spatial Aβ aggregation dynamics in evolving Alzheimer’s disease pathology by imaging stable isotope labeling kinetics
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“Formation and deposition of C-terminally truncated A1-38 occur after initial plaque formation The initiation and progression of amyloid plaque pathology have been suggested to be associated with secretion and aggregation of distinct A peptide truncations, where both C- and N-terminal truncations have been reported (…”
Background
A Mathematical Model of the Impact of Novel Treatments on the AβBurden in the Alzheimer's Brain, CSF and Plasma
Craft, D. (2002) · Bulletin of Mathematical Biology · doi:10.1006/bulm.2002.0304 · Cited by 64
Self-citation
Hyper-expression of human apolipoprotein E4 in astroglia and neurons does not enhance amyloid deposition in transgenic mice
Lesuisse, C. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.22.2525 · Cited by 45
Blood Biomarkers for Alzheimer’s Disease in Down Syndrome
Montoliu‐Gaya, L., Strydom, A., Blennow, K., Zetterberg, H., & Ashton, N. J. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10163639 · Cited by 46
“Amyloid plaques usually occur earlier in DS individuals compared with the general population, and deposits of Aβ in the cortex of DS individuals have been detected as early as at 12 years of age [5].”
Background
Subcellular Changes in Bridging Integrator 1 Protein Expression in the Cerebral Cortex During the Progression of Alzheimer Disease Pathology
Adams, S. L., Tilton, K., Kozubek, J. A., Seshadri, S., & Delalle, I. (2016) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw056 · Cited by 45
“In addition, transcriptome analysis of human brain in trisomy 21 (Down syndrome), a disorder the pathogenesis of which includes 3 copies of APP that causes the early appearance of AD-like pathology (63), revealed possible defects in oligodendrocyte maturation and myelination (64).”
Processing of Mutant β-Amyloid Precursor Protein and the Clinicopathological Features of Familial Alzheimer’s Disease
Bi, C., Bi, S., & Li, B. (2018) · Aging and Disease · doi:10.14336/ad.2018.0425 · Cited by 46
“through the intracellular tau protein [176, 179-182].”
Molecular abnormalities of the brain in Down Syndrome: relevance to Alzheimer’s neurodegeneration
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Stress, Aging, and Neurodegenerative Disorders: Molecular Mechanismsa
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A fibril-specific, conformation-dependent antibody recognizes a subset of Aβ plaques in Alzheimer disease, Down syndrome and Tg2576 transgenic mouse brain
Sarsoza, F. M., Saing, T., Kayed, R., Dahlin, R., Dick, M. B., Broadwater-Hollifield, C., Mobley, S., Lott, I. T., Doran, E. W., Gillen, D. L., et al. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0530-3 · Cited by 44
Observations in APP Bitransgenic Mice Suggest that Diffuse and Compact Plaques Form via Independent Processes in Alzheimer's Disease
Lord, A., Philipson, O., Klingstedt, T., Westermark, G. T., Hammarström, P., Nilsson, K. P. R., & Nilsson, L. N. G. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.01.052 · Cited by 46
“Extracellular diffuse deposits of A ending at amino acid 42 (A x-42) were observed in 12-year-old children, whereas compact plaques with A ending at amino acid 40 (A x-40) were not evident until age 30 years.(42,43) Because diffuse A deposits predate compact plaques in brains in patients with Down’s syndrome, it has b…”
Background
Different aspects of Alzheimer’s disease-related amyloid β-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia
Thal, D. R., Ronisz, A., Tousseyn, T., Upadhaya, A. R., Balakrishnan, K., Vandenberghe, R. R., Vandenbulcke, M., Arnim, C. A. F. V., Otto, M., Beach, T. G., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0837-9 · Cited by 44
“Aβ pathology can be described by 1. the topographical distribution of Aβ plaques [11, 71, 72] or CAA-affected vessels in the brain [68], 2. measures of quantity in a given brain region (morphological Aβ plaque loads, biochemically detected measures of Aβ levels (ELISA, western blotting)) [2, 3, 14, 41, 46, 50, 57, 59,…”
BackgroundResult
Metal homeostasis in Alzheimer’s disease
White, A. R., Barnham, K. J., & Bush, A. I. (2006) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.6.5.711 · Cited by 42
Molecular and Cellular Basis for Anti-Amyloid Therapy in Alzheimer Disease
Gandy, S., Martins, R. N., & Buxbaum, J. D. (2003) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-200310000-00011 · Cited by 41
“thought to initiate A-beta accumulation and plaque formation in all forms of the disease.(10,11) The molecule discovered by Peter Hyslop and colleagues(7) in 1995 and named “presenilin,” since it is responsible for most early onset FAD, plays a crucial role in gamma-”
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Cerebrospinal fluid biomarkers for Alzheimer's disease in Down syndrome
Dekker, A. D., Fortea, J., Blesa, R., & Deyn, P. P. D. (2017) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2017.02.006 · Cited by 42
“formation of more compacted fibrillary plaques that contain Ab1–40 as well [6].”
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Profiles of β-Amyloid Peptides and Key Secretases in Brain Autopsy Samples Differ with Sex and APOE ε4 Status: Impact for Risk and Progression of Alzheimer Disease
Nyarko, J. N. K., Quartey, M. O., Pennington, P. R., Heistad, R. M., Dea, D., Poirier, J., Baker, G. B., & Mousseau, D. D. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.01.005 · Cited by 48
Differential effects of Down's syndrome and Alzheimer's neuropathology on default mode connectivity
Wilson, L. R., Vatansever, D., Annus, T., Williams, G. B., Hong, Y. T., Fryer, T. D., Nestor, P. J., Holland, A. J., & Zaman, S. H. (2019) · Human Brain Mapping · doi:10.1002/hbm.24720 · Cited by 43
“Indeed, histological studies have found Aβ plaques in the brains of children and teenagers with Down's syndrome (Lemere et al., 1996; Leverenz & Raskind, 1998), while this neuropathology appears in nearly 100% of people with Down's syndrome over 40 years of age (Mann, 1988).”
Background
The chromosome 21 transcription factor ETS2 transactivates the β-APP promoter: implications for Down syndrome
Wolvetang, E. J., Bradfield, O., Tymms, M. J., Zavarsek, S., Hatzistavrou, T., Kola, I., & Hertzog, P. J. (2003) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(03)00121-0 · Cited by 42
Early dysregulation of hippocampal proteins in transgenic rats with Alzheimer's disease-linked mutations in amyloid precursor protein and presenilin 1
Vercauteren, F., Clerens, S., Roy, L., Hamel, N., Arckens, L., Vandesande, F., Alhonen, L. I., Jänne, J., Szyf, M., & Cuello, A. C. (2004) · Molecular Brain Research · doi:10.1016/j.molbrainres.2004.10.012 · Cited by 40
Regulation of Alzheimer β-amyloid precursor trafficking and metabolism11Portions of this review have previously appeared in Trends in Endocrinology and Metabolism and are reprinted here with the permission of Elsevier Publishing.
Gandy, S., & Petanceska, S. S. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(00)00031-4 · Cited by 40
Nerve growth factor (NGF) pathway biomarkers in Down syndrome prior to and after the onset of clinical Alzheimer's disease: A paired CSF and plasma study
Pentz, R., Iulita, M. F., Ducatenzeiler, A., Videla, L., Benejam, B., Carmona‐Iragui, M., Blesa, R., Lleó, A., Fortea, J., & Cuello, A. C. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12229 · Cited by 40
Alzheimer's disease neuropathology and its estimation with fluid and imaging biomarkers
Thal, D. R., Poesen, K., Vandenberghe, R. R., & Meyer, S. D. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00819-y · Cited by 55
“In patients with Down syndrome, amyloid plaque pathology starts to develop as early as 12 years of age [66].”
Critical Issues for Successful Immunotherapy in Alzheimers Disease: Development of Biomarkers and Methods for Early Detection and Intervention
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Brain Expression of Presenilins in Sporadic and Early-onset, Familial Alzheimer’s Disease
Mathews, P. M., Cataldo, A. M., Kao, B. H., Rudnicki, A., Qin, X., Yang, J. L., Jiang, Y., Picciano, M., Hulette, C., Lippa, C. F., et al. (2000) · Molecular Medicine · doi:10.1007/bf03401825 · Cited by 40
Mutant Presenilin 1 Increases the Levels of Alzheimer Amyloid β‐Peptide Aβ42 in Late Compartments of the Constitutive Secretory Pathway
Petanceska, S. S., Seeger, M., Checler, F., & Gandy, S. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0741878.x · Cited by 40
Tau load is associated with apolipoprotein E genotype and the amount of amyloid β protein, Aβ40, in sporadic and familial Alzheimer's disease
Thaker, U., McDonagh, A. M., Iwatsubo, T., Lendon, C. L., Pickering-Brown, S. M., & Mann, D. M. A. (2003) · Neuropathology and Applied Neurobiology · doi:10.1046/j.1365-2990.2003.00425.x · Cited by 39
Midlife mental distress and risk for dementia up to 27 years later: the Nord-Trøndelag Health Study (HUNT) in linkage with a dementia registry in Norway
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“There is evidence that pathology related to Alzheimer’s disease starts decades before clinical diagnosis [53,54].”
Background
Dynamics of plasma biomarkers in Down syndrome: the relative levels of Aβ42 decrease with age, whereas NT1 tau and NfL increase
Mengel, D., Liu, W., Glynn, R. J., Selkoe, D. J., Strydom, A., Lai, F., Rosas, H. D., Torres, A., Patsiogiannis, V., Skotko, B. G., et al. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00593-7 · Cited by 36
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Immunotherapeutic approaches for Alzheimer’s disease in transgenic mouse models
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“(2) Down’s syndrome, where there is an extra copy of the APP gene due to trisomy 21, is associated with AD related pathology at a very early age (Lemere et al. 1996).”
BackgroundSelf-citation
A$beta;1-15 is less immunogenic than A$beta;1-40/42 for intranasal immunization of wild-type mice but may be effective for ?boosting?
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Comparison of the aggregation properties, secondary structure and apoptotic effects of wild‐type, Flemish and Dutch N‐terminally truncated amyloid β peptides
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“The presence of diffuse plaques suggest that N-terminally truncated Ab peptides could have an important role in the parenchymal deposition, as has been observed in Down's syndrome (Lemere et al., 1996; Saido et al., 1996).”
Background
Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease
Eleuteri, S., Giovanni, S. D., Rockenstein, E. M., Mante, M., Adame, A., Trejo, M., Wrasidlo, W., Wu, F., Fraering, P. C., Masliah, E., et al. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.017 · Cited by 40
“…of differentmorphologies, including spherical, chain-like, and annular oligomers have been observed during Aβ fibril formation in vitro (Jan et al., 2010b), and similar structures were identified during post-mortem biochemical analysis of AD brains (Lemere et al., 1996; Lesne et al., 2006).”
Background
Aβ species, including IsoAsp23 Aβ, in Iowa-type familial cerebral amyloid angiopathy
Shin, Y., Cho, H. J., Fukumoto, H., Shimizu, T., Shirasawa, T., Greenberg, S. M., & Rebeck, W. G. (2003) · Acta Neuropathologica · doi:10.1007/s00401-002-0639-0 · Cited by 37
“This model is supported by studies of brains of Down’s syndrome individuals of different ages [ 23 ].”
Method

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.
ORCID: Lemere, C.A.
Blusztajn, J.K.
Yamaguchi, H.
Saido, T.C.
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)
DOI: 10.1006/nbdi.1996.0003
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: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 2305 d)
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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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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