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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High-Affinity Rabbit Monoclonal Antibodies Specific for Amyloid Peptides Amyloid-β40 and Amyloid-β42
Miller, D. L., Potempska, A., Węgiel, J., & Mehta, P. D. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101341 · Cited by 24
“Overexpression of A PP, overproduction of A , and early intracellular accumulation of A [30] have been considered to be the foundations for this early onset of AD pathology and functional deterioration [31, 32].”
Background
Boosting with intranasal dendrimeric Aβ1–15 but not Aβ1–15 peptide leads to an effective immune response following a single injection of Aβ1–40/42 in APP-tg mice
Seabrook, T. J., Jiang, L., Thomas, K., & Lemere, C. A. (2006) · Journal of Neuroinflammation · doi:10.1186/1742-2094-3-14 · Cited by 23
Self-citation
Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models
Kumar, S., Lemere, C. A., & Walter, J. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00959-w · Cited by 24
“Indeed, abundant levels of aminoterminally modified and truncated Aβ peptides have been detected in DS brains previously [30, 35, 36, 54, 55].”
Self-citation
Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches
Farrell, C., Mumford, P., & Wiseman, F. K. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.909669 · Cited by 22
“Typically however, Aβ accumulation begins in the teens and early-twenties; extracellular amyloid accumulation is seen in the brain parenchyma, beginning as diffuse plaques (made of non-fibrillary deposits), followed by the presence of densecore plaques over the next decade (Ropper and Williams, 1980; Mann and Esiri, 1…”
Background
Soluble and insoluble protein aggregates, endoplasmic reticulum stress, and vascular dysfunction in Alzheimer’s disease and cardiovascular diseases
Waigi, E. W., Webb, R. C., Moss, M. A., Uline, M. J., McCarthy, C. G., & Wenceslau, C. F. (2023) · GeroScience · doi:10.1007/s11357-023-00748-y · Cited by 26
Cerebrospinal fluid Aβ 42 levels and APP processing pathway genes in Parkinson's disease
Bekris, L. M., Tsuang, D. W., Peskind, E. R., Yu, C., Montine, T. J., Zhang, J., Zabetian, C. P., & Leverenz, J. B. (2015) · Movement Disorders · doi:10.1002/mds.26172 · Cited by 22
Diverse Molecular Targets for Therapeutic Strategies in Alzheimer's Disease
Han, S.-H., & Mook‐Jung, I. (2014) · Journal of Korean Medical Science · doi:10.3346/jkms.2014.29.7.893 · Cited by 23
“Especially, pyroglutamyl modification in N-terminus of Aβ is critical alteration because pyroglutamated Aβ (pGlu-Aβ) species readily accumulated into senile plaque and vasculature deposit due to increased stability and aggregation velocity (47-49).”
Background
Cerebral amyloid angiopathy as a cause of an extensive brain hemorrhage in adult patient with Down's syndrome - a case report.
Mendel, T. A., Bertrand, E., Szpak, G. M., Stępień, T., & Wierzba‐Bobrowicz, T. (2010) · PubMed · Cited by 23
A Review of Biomarkers for Alzheimer’s Disease in Down Syndrome
Lee, N., Chien, Y., & Hwu, W. (2017) · Neurology and Therapy · doi:10.1007/s40120-017-0071-y · Cited by 23
Presenilins, β-amyloid precursor protein and the molecular basis of Alzheimer's disease
Selkoe, D. J. (2001) · Clinical Neuroscience Research · doi:10.1016/s1566-2772(00)00016-5 · Cited by 24
Self-citation
Acetylcholinesterase induces the expression of the β-amyloid precursor protein in glia and activates glial cells in culture
Rommy von Bernhardi, M., Ramírez, G., Ferrari, G. V. D., & Inestrosa, N. C. (2003) · Neurobiology of Disease · doi:10.1016/j.nbd.2003.08.014 · Cited by 23
Role of metal ions in the cognitive decline of Down syndrome
Malakooti, N., Pritchard, M. A., Adlard, P. A., & Finkelstein, D. I. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00136 · Cited by 20
“The presence of enlarged endosomes precedes Aβ peptide deposition which appears at around 12 years of age in the form of diffuse plaques, followed by mature Aβ plaques when the individuals are in their 30’s (Lemere et al., 1996).”
Background
Exosome release and cargo in Down syndrome
Hamlett, E. D., LaRosa, A., Mufson, E. J., Fortea, J., Ledreux, A., & Granholm, A. (2019) · Developmental Neurobiology · doi:10.1002/dneu.22712 · Cited by 21
“Diffuse amyloid plaques have been described as early as age fifteen in post mortem brain samples from people with DS (Lemere et al., 1996), and elevated Aβ levels are observed in plasma already in young adults with DS (Mehta et al.”
Background
The brain in Down syndrome
Seidl, R., Cairns, N. J., & Lübec, G. (2001) · Springer eBooks · doi:10.1007/978-3-7091-6262-0_20 · Cited by 21
Comparison of longitudinal Aβ in nondemented elderly and Down syndrome
Tudorascu, D., Anderson, S., Minhas, D. S., Yu, Z., COMER, D. M., Lao, P. J., Hartley, S. L., Laymon, C. M., Snitz, B. E., Lopresti, B. J., et al. (2018) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.09.030 · Cited by 22
Alzheimer’s disease is an inherent, natural part of human brain aging: an integrated perspective
Ferrer, I. (2022) · Free Neuropathology · doi:10.17879/freeneuropathology-2022-3806 · Cited by 25
Using Drosophila amyloid toxicity models to study Alzheimer's disease
Tsintzas, E., & Niccoli, T. (2024) · Annals of Human Genetics · doi:10.1111/ahg.12554 · Cited by 20
“The inclusion of two additional hydrophobic residues in A β 1–42 leads to the formation of β -sheet-rich structures, which further aggregate as neurotoxic plaques in the brain (Chen et al., 2017; Lemere et al., 1996; Quartey et al., 2021).”
Chemical imaging delineates Aβ plaque polymorphism across the Alzheimer’s disease spectrum
Koutarapu, S., Ge, J., Dulewicz, M., Srikrishna, M., Szadziewska, A., Wood, J. I., Blennow, K., Zetterberg, H., Michno, W., Ryan, N. S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59085-7 · Cited by 29
Apolipoprotein E increases cell association of amyloid-β 40 through heparan sulfate and LRP1 dependent pathways
O'Callaghan, P. W., Noborn, F., Sehlin, D., Li, J., Lannfelt, L., Lindahl, U., & Zhang, X. (2014) · Amyloid · doi:10.3109/13506129.2013.879643 · Cited by 20
“Previous studies have demonstrated the co-deposition of Ab and ApoE in amyloid deposits of AD and DS brain [36,37].”
Background
Refining the amyloid β peptide and oligomer fingerprint ambiguities in Alzheimer’s disease: Mass spectrometric molecular characterization in brain, cerebrospinal fluid, blood, and plasma
Michno, W., Blennow, K., Zetterberg, H., & Brinkmalm, G. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15466 · Cited by 18
Serum NGAL is Associated with Distinct Plasma Amyloid-β Peptides According to the Clinical Diagnosis of Dementia in Down Syndrome
Naudé, P. J. W., Dekker, A. D., Coppus, A. M. W., Vermeiren, Y., Eisel, U. L. M., van Duijn, C. M., Dam, D. V., & Deyn, P. P. D. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-142514 · Cited by 20
“During the later stages in life (around 50 years), Aβ40 accumulation gradually increases in mature plaques and, moreover, it is the predominant Aβ species in cerebral amyloid angiopathy in DS (Iwatsubo et al., 1995; Lemere et al., 1996).”
The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer's disease
Portelius, E., Fortea, J., Molinuevo, J. L., Gustavsson, M. K., Andréasson, U., & Sánchez‐Valle, R. (2012) · Molecular Medicine Reports · doi:10.3892/mmr.2012.774 · Cited by 19
“Data supporting the view that life-long amyloid precursor protein (APP) overexpression triggers Aβ deposition and neurodegeneration come from studies on Down's syndrome patients and the finding of a duplication of the APP locus in a certain familial form of AD (2,3).”
Background
Metabolic and Growth Rate Alterations in Lymphoblastic Cell Lines Discriminate Between Down Syndrome and Alzheimer’s Disease
Coskun, P. E., Helguera, P. R., Nemati, Z., Bohannan, R. C., Thomas, J., Samuel, S. E., Argueta, J., Doran, E. W., Wallace, D. C., Lott, I. T., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160278 · Cited by 19
Searching for new pharmacological targets for the treatment of Alzheimer's disease in Down syndrome
Caraci, F., Iulita, M. F., Pentz, R., Flores Aguilar, L., Orciani, C., Barone, C., Romano, C., Drago, F., & Cuello, A. C. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.10.004 · Cited by 18
Comparison of resting-state EEG between adults with Down syndrome and typically developing controls
Hamburg, S., Bush, D., Strydom, A., & Startin, C. M. (2021) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-021-09392-z · Cited by 18
“However, amyloid deposition can occur from childhood in DS [36] and therefore results may be confounded by this.”
State-switching and high-order spatiotemporal organization of dynamic functional connectivity are disrupted by Alzheimer’s disease
Arbabyazd, L., Petkoski, S., Breakspear, M. J., Solodkin, A., Battaglia, D. A., & Jirsa, V. (2023) · Network Neuroscience · doi:10.1162/netn_a_00332 · Cited by 23
Down Syndrome, Ageing and Epigenetics
Gensous, N., Franceschi, C., Salvioli, S., Garagnani, P., & Bacalini, M. G. (2019) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-981-13-3681-2_7 · Cited by 19
Neuroinflammation and Alteration of the Blood-Brain Barrier in Alzheimer´s Disease
Soto-Rojas, L. O., de la Cruz‐López, F., Ontiveros‐Torres, M. Á., Viramontes‐Pintos, A., Cárdenas‐Aguayo, M. D. C., Meraz‐Ríos, M. A., Salinas‐Lara, C., Florán, B., & Luna‐Muñoz, J. (2015) · InTech eBooks · doi:10.5772/60024 · Cited by 21
“[27].”
Apolipoprotein E Proteinopathy Is a Major Dementia-Associated Pathologic Biomarker in Individuals with or without the APOE Epsilon 4 Allele
Gal, J., Katsumata, Y., Zhu, H., Srinivasan, S., Chen, J., Johnson, L. A., Wang, W.-X., Golden, L. R., Wilcock, D. M., Jicha, G. A., et al. (2022) · The American Journal of Pathology · doi:10.1016/j.ajpath.2021.11.013 · Cited by 17
N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer’s Disease
Bayer, T. A. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.710579 · Cited by 19
Adapting prescribing criteria for amyloid‐targeted antibodies for adults with Down syndrome
Hillerstrom, H., Fisher, R. A., Janicki, M. P., Chicoine, B. A., Christian, B. T., Esbensen, A. J., Esralew, L., Fortea, J., Hartley, S. L., Hassenstab, J. J., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13778 · Cited by 17
Rapid Improvement of Canine Cognitive Dysfunction with Immunotherapy designed for Alzheimer's Disease
Bosch, M. N., Gimeno‐Bayón, J., Rodríguez, M. J., Pugliese, M., & Mahy, N. (2013) · Current Alzheimer Research · doi:10.2174/15672050113109990129 · Cited by 17
“Different dynamic [3] and Aβ aggregation progression processes [46–49] may explain these differences with the studies in human beings.”
Background
Down’s syndrome and Alzheimer’s disease: two sides of the same coin
Potter, H. (2007) · Future Neurology · doi:10.2217/14796708.3.1.29 · Cited by 17
The Amyloid β Protein
Lazo, N. D., Maji, S. K., Fradinger, E. A., Bitan, G., & Teplow, D. B. (2005) · Wiley eBooks · doi:10.1002/9783527619344.ch17 · Cited by 18
Regulation of Alzheimer ß-Amyloid Precursor Trafficking and Metabolism
Gandy, S., & Petanceska, S. S. (2001) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-1249-3_7 · Cited by 16
Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders
Bartesaghi, R., Vicari, S., & Mobley, W. C. (2022) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-041521-103641 · Cited by 18
Cell models for Down syndrome-Alzheimer’s disease research
Wu, Y., West, N. R., Bhattacharyya, A., & Wiseman, F. K. (2022) · Neuronal Signaling · doi:10.1042/ns20210054 · Cited by 17
Distinct Molecular Signatures of Amyloid-Beta and Tau in Alzheimer’s Disease Associated with Down Syndrome
Ichimata, S., Martínez-Valbuena, I., Lee, S., Li, J., Karakani, A. M., & Kovács, G. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411596 · Cited by 15
Therapeutic Potential of Vaccines for Alzheimer‘s Disease
Shah, S., & Federoff, H. J. (2011) · Immunotherapy · doi:10.2217/imt.10.94 · Cited by 15
The Genetics of Alzheimer’s Disease and Parkinson’s Disease
Bekris, L. M., Yu, C., Bird, T. D., & Tsuang, D. W. (2010) · Advances in neurobiology · doi:10.1007/978-1-4419-7104-3_21 · Cited by 16
“The APP gene was mapped to chromosome 21q which accounts for the observation that Down syndrome patients (trisomy 21) develop amyloid deposits and the neuropathological features of AD in their 40 s (Giaccone et al., 1989; Iwatsubo et al., 1994; Lemere et al., 1996; Mann et al., 1989).”
Background
The presubiculum is preserved from neurodegenerative changes in Alzheimer’s disease
Murray, C. E., Gami‐Patel, P., Gkanatsiou, E., Brinkmalm, G., Portelius, E., Wirths, O., Heywood, W., Blennow, K., Ghiso, J. A., Holton, J. L., et al. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0563-8 · Cited by 15
“These modified forms of Aβ are frequently detected in plaques of all AD cases [33, 44, 60].”
Background
The AMY Antigen Co-Occurs with Aβ and Follows Its Deposition in the Amyloid Plaques of Alzheimer's Disease and Down Syndrome
Lemere, C. A., Grenfell, T. J., & Selkoe, D. J. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65095-x · Cited by 15
“Details of the immunostaining protocol have been previously described.(5) Double labeling was accomplished using the horseradish peroxidase/DAB kit to detect the first primary antibody and the alkaline phosphatase ABC kit with Vector Red substrate (Vector Laboratories) to detect the second primary antibody.”
BackgroundMethodInfluentialSelf-citation
Increased cerebral microbleeds and cortical superficial siderosis in pediatric patients with Down syndrome
Schoeppe, F., Rossi, A., Levin, J., Reiser, M. F., Stoecklein, S., & Ertl-Wagner, B. B. (2018) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2018.09.004 · Cited by 14

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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