Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome
Open accessAbstract
To study the pathogenesis of central nervous system abnormalities in Down syndrome (DS), we have analyzed a new genetic model of DS, the partial trisomy 16 (Ts65Dn) mouse. Ts65Dn mice have an extra copy of the distal aspect of mouse chromosome 16, a segment homologous to human chromosome 21 that contains much of the genetic material responsible for the DS phenotype. Ts65Dn mice show developmental delay during the postnatal period as well as abnormal behaviors in both young and adult animals that may be analogous to mental retardation. Though the Ts65Dn brain is normal on gross examination, there is age-related degeneration of septohippocampal cholinergic neurons and astrocytic hypertrophy, markers of the Alzheimer disease pathology that is present in elderly DS individuals. These findings suggest that Ts65Dn mice may be used to study certain developmental and degenerative abnormalities in the DS brain.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The ApoE gene is associated with increased risk of AD and is not located on the triplicated segment of MMU16, but it is overexpressed to higher levels in Ts65Dn mice than predicted on the basis of gene dosage.
“Finally, the ApoE gene, which is associated with increased risk of AD (Corder et al., 1993), is not located on the triplicated segment of MMU16, but it is overexpressed to higher levels in Ts65Dn mice than is predicted on the basis of gene dosage (Holtzman et al., 1996).”
From <i>App</i>Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome (2003) · cites this paper as Holtzman et al., 1996
Ts65Dn mice do not deposit β-amyloid.
“Unlike what occurs in human disorders, however, Ts65Dn mice do not deposit -amyloid.”
From <i>App</i>Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome (2003) · cites this paper as Holtzman et al., 1996
Basal forebrain neurons in Ts65Dn mice later develop aging-related atrophy and degenerative changes, as in AD and DS.
“Ts65Dn mice also exhibit age-related atrophy and neurodegeneration of basal forebrain cholinergic neurons (BFCNs) and extensive astrocytic hypertrophy resembling these aspects of the neuropathology in AD and DS (Holtzman et al., 1996;Cooper et al., 2001).”
From <i>App</i>Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome (2003) · cites this paper as Holtzman et al., 1996
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein
Games, D., Adams, D., Alessandrini, R., Barbour, R., Borthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al. (1995) · Nature · doi:10.1038/373523a0 · Cited by 2,516 · see citing works
Astrocytes synthesize apolipoprotein E and metabolize apolipoprotein E-containing lipoproteins
Pitas, R. E., Boyles, J. K., Lee, S. H., Foss, D., & Mahley, R. W. (1987) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(87)90295-5 · Cited by 693 · see citing works
Flagged first, then by citations
Research works printed but not linked: 8
- [1]Epstein, C. J. (1986) Consequences of Chromosome Imbalance: Principals, Mechanisms, and Models (Cambridge Univ. Press, New York).
- [8]Davisson, M. T., Schmidt, C., Reeves, R. H., Irving, N. G., Akeson, E. C., Harris, B. S. & Bronson, R. T. (1993) in Segmental Trisomy as a Mouse Model for Down Syndrome , ed. Epstein, C. J. (Wiley-Liss, New York), pp. 117-133.
- [15]Calamandrei, G., Ricceri, L. & Valanzano, A. (1996) Brain Res ., in press.
- [27]Griffin, W. S. T., Stanley, L. C., Ling, C., White, L., MacLeod, V., Perrot, L. J., White, C. L. & Araoz, C. (1989) Proc. Natl. Acad. Sci. USA 86, 7611-7615.
- [34]Wishart, J. G. (1988) in Early Learning in Infants and Young Children with Down Syndrome , ed. Nadel, L. (MIT Press, Cambridge, MA), pp. 7-50.
- [36]Olton, D. S., Givens, B. S., Markowska, A. L., Shapiro, M. & Golski, S. (1991) in Mnemonic Functions of the Cholinergic Septohippocampal System , eds. Squire, L. R., Weinberger, N. M. & McGaugh, J. L. (Oxford Univ. Press, London).
- [41]Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L.-Y., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D. & Roses, A. D. (1993) Proc. Natl. Acad. Sci. USA 90, 8098-8102.
- [47]Lamb, B. T., Sisodia, S. S., Lawler, A. M., Slunt, H. H., Kitt, C. A., Kearns, W. G., Pearson, P. L., Price, D. L. & Gearhart, J. D. (1993) Nat. Genet. 5, 22-30.
Cited by
Sorted by citations
Salehi, A., Delcroix, J.-D., Belichenko, P. V., Zhan, K., Wu, C., Valletta, J. S., Takimoto-Kimura, R., Kleschevnikov, A. M., Sambamurti, K., Chung, P. P., et al. (2006) · Neuron · doi:10.1016/j.neuron.2006.05.022 · Cited by 543 · see citing works
Self-citationCognitive deficits and associated neurological complications in individuals with Down's syndrome
Lott, I. T., & Dierssen, M. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70112-5 · Cited by 484 · see citing works
Sago, H., Carlson, E. J., Smith, D. J., Kilbridge, J., Rubin, E. M., Mobley, W. C., Epstein, C. J., & Huang, T.-T. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6256 · Cited by 382 · see citing works
Self-citationCataldo, A. M., Petanceska, S., Peterhoff, C. M., Terio, N. B., Epstein, C. J., Villar, A., Carlson, E. J., Staufenbiel, M., & Nixon, R. A. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-17-06788.2003 · Cited by 241 · see citing works
Self-citationNeurological phenotypes for Down syndrome across the life span
Lott, I. T. (2012) · Progress in Brain Research · doi:10.1016/b978-0-444-54299-1.00006-6 · Cited by 225 · see citing works
Altered long-term potentiation in the young and old Ts65Dn mouse, a model for down syndrome
Siarey, R. J., Stoll, J., Rapoport, S. I., & Galdzicki, Z. (1997) · Neuropharmacology · doi:10.1016/s0028-3908(97)00157-3 · Cited by 222 · see citing works
DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects
Ahn, K.-J., Jeong, H. K., Choi, H.-S., Ryoo, S.-R., Kim, Y. J., Goo, J.-S., Choi, S.-Y., Han, J.-S., Ha, I., & Song, W.-J. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.12.006 · Cited by 220 · see citing works
Costa, A. C. S., & Grybko, M. J. (2005) · Neuroscience Letters · doi:10.1016/j.neulet.2005.03.031 · Cited by 174 · see citing works
Martı́nez-Cué, C., Baamonde, C., Lumbreras, M., Paz, J., Davisson, M. T., Schmidt, C., Dierssen, M., & Flórez, J. (2002) · Behavioural Brain Research · doi:10.1016/s0166-4328(02)00026-8 · Cited by 166 · see citing works
Epigenetic control of neurobehavioural plasticity: the role of neurotrophins
Branchi, I., Francia, N., & Alleva, E. (2004) · Behavioural Pharmacology · doi:10.1097/00008877-200409000-00006 · Cited by 133 · see citing works
Self-citationCommunication breaks-Down: From neurodevelopment defects to cognitive disabilities in Down syndrome
Contestabile, A., Benfenati, F., & Gasparini, L. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.01.003 · Cited by 134 · see citing works
Traffic at the intersection of neurotrophic factor signaling and neurodegeneration
Salehi, A., Delcroix, J.-D., & Mobley, W. C. (2003) · Trends in Neurosciences · doi:10.1016/s0166-2236(02)00038-3 · Cited by 131 · see citing works
Self-citationAziz, N. M., Guedj, F., Pennings, J. L. A., Olmos-Serrano, J. L., Siegel, A., Haydar, T. F., & Bianchi, D. W. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.031013 · Cited by 118 · see citing works
Fagan, A. M., Murphy, B. A., Patel, S. N., Kilbridge, J. F., Mobley, W. C., Bu, G., & Holtzman, D. M. (1998) · Experimental Neurology · doi:10.1006/exnr.1998.6818 · Cited by 116 · see citing works
Self-citationHyde, L. A., Frisone, D. F., & Crnic, L. S. (2001) · Behavioural Brain Research · doi:10.1016/s0166-4328(00)00313-2 · Cited by 108 · see citing works
Di Domenico, F., Tramutola, A., Foppoli, C., Head, E., Perluigi, M., & Butterfield, D. A. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.08.009 · Cited by 89 · see citing works
Pérez-Cremades, D., Hernández, S., Blasco-Ibáñez, J. M., Crespo, C., Nacher, J., & Varea, E. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0376-9 · Cited by 85 · see citing works
Absence of Prenatal Forebrain Defects in the Dp(16)1Yey/+ Mouse Model of down Syndrome.
Goodliffe, J. W., Olmos-Serrano, J. L., Aziz, N. M., Pennings, J. L. A., Guedj, F., Bianchi, D. W., & Haydar, T. F. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.2513-15.2016 · Cited by 65 · see citing works
Treating enhanced GABAergic inhibition in Down syndrome: Use of GABA α5-selective inverse agonists
Martínez-Cué, C., Delatour, B., & Potier, M.-C. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2013.12.008 · Cited by 58 · see citing works
Shaw, P. R., Klein, J. A., Aziz, N. M., & Haydar, T. F. (2020) · Disease Models & Mechanisms · doi:10.1242/dmm.046243 · Cited by 45 · see citing works
Illouz, T., Madar, R., Biragyn, A., & Okun, E. (2019) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2018.10.004 · Cited by 22 · see citing works
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 · see citing works
- Authors
- Holtzman, D. M., Santucci, D., Kilbridge, J., Chua-Couzens, J., Fontana, D. J., Daniels, S. E., Johnson, R. M., Chen, K., Sun, Y., Carlson, E., Alleva, E., Epstein, C. J., & Mobley, W. C.
- Affiliations
- Washington University in St. Louis (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1996-11-12
- Volume
- 93
- Issue
- 23
- Pages
- 13333-13338
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC24093
- OpenAlex
- W2099268443
- Cited by
- 448
- References
- 2
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 17 · 2023: 15 · 2022: 16 · 2021: 12 · 2020: 14 · 2019: 13 · 2018: 13 · 2017: 16 · 2016: 10 · 2015: 16 · 2014: 16 · 2013: 15 · 2012: 23
- FWCI
- 12.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Federation for Aging Research
- National Down Syndrome Society
- National Institutes of Health (5r01ag010672-05)
- National Institute on Aging (AG00445, AG10672, AG-08938, P01AG008938)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Down syndrome, Ts65Dn mouse model, mouse model, neurodevelopmental delay, age-related neurodegeneration, Alzheimer disease pathology, intellectual disability, chromosome 21
- MeSH terms
- Aging, Animals, Avoidance Learning, Brain, Chromosome Mapping, Disease Models, Animal, Down Syndrome, Female, Humans, Learning, Male, Mice, Inbred Strains, Mice, Neurologic Mutants, Motor Activity, Nerve Degeneration, Stereotyped Behavior, Trisomy, Vocalization, Animal, Maze Learning, Mice
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
