CoChat
Sign Up
Cited by 207Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Gene delivery of human apolipoprotein E alters brain Aβ burden in a mouse model of Alzheimer's disease

Open access
Dodart, Jean-Cosme, Marr, Robert A., Koistinaho, Milla, Gregersen, Beth M., Malkani, Seema, Verma, Inder M., Paul, Steven M.·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0409072102PMC PMC544620
Open this paper in CoChat — free account

Abstract

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the ε4 allele increasing and the ε2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-β peptide (Aβ) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal Aβ and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Aβ 1–42 levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Aβ burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Aβ burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Aβ burden and the subsequent development of neuritic plaques.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.0409072102

Cites

43 of 43 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • Studies with a lentiviral vector expressing APOE2 delivered directly to the hippocampus of a transgenic Alzheimer's disease mouse established a robust protective effect of the APOE2 allele on Alzheimer's disease risk, with an observed rapid, significant reduction in brain amyloid burden and neuritic plaques.

    “Studies with a lentiviral vector expressing APOE2 delivered directly to the hippocampus of a transgenic AD mouse established a robust protective effect of the APOE2 allele on AD risk, with an observed rapid, significant reduction in brain amyloid burden and neuritic plaques.23”

    From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [23]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • One strategy to prevent Alzheimer's disease in APOE4 carriers is to modify the central nervous system genetically to express APOE2, providing the CNS with the protective APOE2 to balance the Alzheimer's disease risk associated with expression of APOE4.

    “Based on these observations, one strategy to prevent AD in APOE4 carriers is to modify the central nervous system (CNS) genetically to express APOE2, providing the CNS with the protective APOE2 to balance the AD risk associated with expression of APOE4.22–26”

    From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [23]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Exogenous E2 markedly decreases amyloid burden in mice.

    “Moving in vivo, other studies have explored vector-mediated delivery to supplement the E4 brain with neuroprotective E2 protein, showing that exogenous E2 markedly decreases amyloid burden in mice9–12.”

    From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [9]

    The Results report that lentiviral delivery of human apoE2 reduced hippocampal Aβ burden in PDAPP mice, including a 61.5% decrease versus controls after three months. The study does not show apoE2 supplementing an apoE4-expressing brain: the mice in the reported apoE2 experiment expressed endogenous mouse apoE. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Human apoE isoform-dependent differences in amyloid plaque deposition in APP-transgenic mice follow the pattern E4 > E3 > E2.

    “we and others have reported human apoE isoform-dependent differences in amyloid plaque deposition in APP-transgenic mice (E4 > E3 > E2) (10-14).”

    From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [12]

    The Results report greater hippocampal Aβ burden with apoE4 than apoE3 in PDAPP mice lacking mouse apoE, and lower burden with apoE2 than apoE3 in mice expressing mouse apoE. They do not establish the full E4 > E3 > E2 ordering for amyloid plaque deposition under the same conditions: apoE2 and apoE3 did not differ in the mice lacking mouse apoE, and apoE4 did not increase burden in mice expressing it. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Viral-vector mediated overexpression of APOE4 isoforms in AD mouse brains accelerates plaque formation.

    “This has also been observed with viral-vector mediated overexpression of APOE4 isoforms in AD mouse brains (Dodart et al, 2005; Hudry et al, 2013; Zhao et al, 2016).”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Dodart et al, 2005

    The Discussion reports that lentiviral apoE4 increased Aβ deposition and congophilic amyloid within five weeks in PDAPP mice lacking mouse apoE. The claim omits that condition: the Results state that apoE4 did not increase hippocampal Aβ burden in PDAPP mice expressing mouse apoE. Page numbers were not available in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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

Flagged first, then by citations

Research works printed but not linked: 42

  1. [1]Hardy, J., Duff, K., Hardy, K. G., Perez-Tur, J. & Hutton, M. (1998) Nat. Neurosci. 1, 355–358. [DOI] [PubMed] [Google Scholar]
  2. [2]Mattson, M. P. (2004) Nature 430, 631–639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. [3]Selkoe, D. J. (2001) Physiol. Rev. 81, 741–766. [DOI] [PubMed] [Google Scholar]
  4. [4]Strittmatter, W. J. & Roses, A. D. (1996) Ann. Rev. Neurosci. 19, 53–77. [DOI] [PubMed] [Google Scholar]
  5. [5]Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L. & Pericak-Vance, M. A. (1993) Science 261, 921–923. [DOI] [PubMed] [Google Scholar]
  6. [6]Rebeck, G. W., Reiter, J. S., Strickland, D. K. & Hyman, B. T. (1993) Neuron 11, 575–580. [DOI] [PubMed] [Google Scholar]
  7. [7]Saunders, A. M., Strittmatter, W. J., Schmechel, D., George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., Rosi, B. L., Gusella, J. F., Crapper-MacLachlan, D. R., Alberts, M. J., et al. (1993) Neurology 43, 1467–1472. [DOI] [PubMed] [Google Scholar]
  8. [8]Schmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B. J., Hulette, C. M., Joo, S. H., Pericak-Vance, M. A., Goldgaber, D. & Roses, A. D. (1993) Proc. Natl. Acad. Sci. USA 90, 9649–9653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. [9]Walker, L. C., Pahnke, J., Madauss, M., Vogelgesang, S., Pahnke, A., Herbst, E. W., Stausske, D., Walther, R., Kessler, C. & Warzok, R. W. (2000) Acta Neuropathol. 100, 36–42. [DOI] [PubMed] [Google Scholar]
  10. [10]Warzok, R. W., Kessler, C., Apel, G., Schwarz, A., Egensperger, R., Schreiber, D., Herbst, E. W., Wolf, E., Walther, R. & Walker, L. C. (1998) Alzheimer Dis. Assoc. Disord. 12, 33–39. [DOI] [PubMed] [Google Scholar]
  11. [11]Corder, E. H. Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D., Gaskell, P. C., Jr., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) Nat Genet. 7, 180–184. [DOI] [PubMed] [Google Scholar]
  12. [12]Mahley, R. W. (1988) Science 240, 622–630. [DOI] [PubMed] [Google Scholar]
  13. [13]Fagan, A. M., Bu, G., Sun, Y., Daugherty, A. & Holtzman, D. M. (1996) J. Biol. Chem. 271, 30121–30125. [DOI] [PubMed] [Google Scholar]
  14. [14]Fagan, A. M. & Holtzman, D. M. (2000) Microsc. Res. Tech. 50, 297–304. [DOI] [PubMed] [Google Scholar]
  15. [15]Jordàn, J., Galindo, M. F., Miller, R. J., Reardon, C. A., Getz, G. S. & LaDu, M. J. (1998) J. Neurosci. 18, 195–204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. [16]Masliah, E., Mallory, M., Ge, N., Alford, M., Veinbergs, I. & Roses, A. D. (1995) Exp. Neurol. 136, 107–122. [DOI] [PubMed] [Google Scholar]
  17. [17]Puttfarcken, P. S., Manelli, A. M., Falduto, M. T., Getz, G. S. & LaDu, M. J. (1997) J. Neurochem. 68, 760–769. [DOI] [PubMed] [Google Scholar]
  18. [18]Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., et al. (1997) Nat. Genet. 17, 263–264. [DOI] [PubMed] [Google Scholar]
  19. [19]Holtzman, D. M., Bales, K. R., Tenkova, T., Fagan, A. M., Parsadanian, M., Sartorius, L. J., Mackey, B., Olney, J., McKeel, D., Wozniak, D. & Paul, S. M. (2000) Proc. Natl. Acad. Sci. USA 97, 2892–2897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. [20]Koistinaho, M., Lin, S., Wu, X., Esterman, M., Koger, D., Hanson, J., Higgs, R., Liu, F., Malkani, S., Bales, K. R. & Paul, S. M. (2004) Nat. Med. 10, 719–726. [DOI] [PubMed] [Google Scholar]
  21. [21]LaDu, M. J., Lukens, J. R., Reardon, C. A. & Getz, G. S. (1997) J. Neurosci. Res. 49, 9–18. [PubMed] [Google Scholar]
  22. [22]Sanan, D. A., Weisgraber, K. H., Russell, S. J., Mahley, R. W., Huang, D., Saunders, A., Schmechel, D., Wisniewski, T., Frangione, B., Roses, A. D., et al. (1994) J. Clin. Invest. 94, 860–869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. [23]Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. [24]Miyoshi, H., Blomer, U., Takahashi, M., Gage, F. H. & Verma, I. M. (1998) J. Virol. 72, 8150–8157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. [25]Dull, T., Zufferey, R., Kelly, M., Mandel, R. J., Nguyen, M., Trono, D. & Naldini, L. (1998) J. Virol. 72, 8463–8471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. [26]Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al. (1995) Nature 373, 523–527. [DOI] [PubMed] [Google Scholar]
  27. [27]Dodart, J. C., Bales, K. R., Gannon, K. S., Greene, S. J., DeMattos, R. B., Mathis, C., DeLong, C. A., Wu, S., Wu, X., Holtzman, D. M. & Paul, S. M. (2002) Nat. Neurosci. 5, 452–457. [DOI] [PubMed] [Google Scholar]
  28. [28]Sullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., Quarfordt, S. H. & Maeda, N. (1997) J. Biol. Chem. 272, 17972–17980. [DOI] [PubMed] [Google Scholar]
  29. [29]Sullivan, P. M. Mezdour, H., Quarfordt, S. H. & Maeda, N. (1998) J. Clin. Invest. 102, 130–135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. [30]Zannis, V. I., VanderSpek, J. & Silverman, D. (1986) J. Biol. Chem. 261, 13415–13421. [PubMed] [Google Scholar]
  31. [31]Blomer, U., Naldini, L., Kafri, T., Trono, D., Verma, I. M. & Gage, F. H. (1997) J. Virol. 71, 6641–6649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. [32]Naldini, L., Blomer, U., Gage, F. H., Trono, D. & Verma, I. M. (1996) Proc. Natl. Acad. Sci. USA 93, 11382–11388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. [33]Laws, S. M., Hone, E., Gandy, S. & Martins, R. N. (2003) J. Neurochem. 84, 1215–1236. [DOI] [PubMed] [Google Scholar]
  34. [34]Beffert, U., Danik, M., Krzywkowski, P., Ramassamy, C., Berrada, F. & Poirier, J. (1998) Brain Res. Rev. 27, 119–142. [DOI] [PubMed] [Google Scholar]
  35. [35]Xu, P. T., Gilbert, J. R., Qiu, H. L., Ervin, J., Rothrock-Christian, T. R., Hulette, C. & Schmechel, D. E. (1999) Am. J. Pathol. 154, 601–611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. [36]Fagan, A. M., Watson, M., Parsadanian, M., Bales, K. R., Paul, S. M. & Holtzman, D. M. (2002) Neurobiol. Dis. 9, 305–318. [DOI] [PubMed] [Google Scholar]
  37. [37]Dodart, J. C., Mathis, C., Saura, J., Bales, K. R., Paul, S. M. & Ungerer, A. (2000) Neurobiol. Dis. 7, 71–85. [DOI] [PubMed] [Google Scholar]
  38. [38]Lanz, T. A., Carter, D. B. & Merchant, K. M. (2003) Neurobiol. Dis. 13, 246–253. [DOI] [PubMed] [Google Scholar]
  39. [39]Nakagawa, Y., Nakamura, M., McIntosh, T. K., Rodriguez, A., Berlin, J. A., Smith, D. H., Saatman, K. E., Raghupathi, R., Clemens, J., Saido, T. C., et al. (1999) J. Comp. Neurol. 411, 390–398. [PubMed] [Google Scholar]
  40. [40]Redwine, J. M., Kosofsky, B., Jacobs, R. E., Games, D., Reilly, J. F., Morrison, J. H., Young, W. G. & Bloom, F. E. (2003) Proc. Natl. Acad. Sci. USA 100, 1381–1386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. [41]Wu, C.-C., Chawla, F., Games, D., Rydel, R. E., Freedman, S., Schenk, D., Young, W. G., Morrison, J. H. & Bloom, F. E. (2004) Proc. Natl. Acad. Sci. USA 101, 7141–7146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. [42]Marr, R. A., Rockenstein, E., Mukherjee, A., Kindy, M. S., Hersh, L. B., Gage, F. H., Verma, I. M. & Masliah, E. (2003) J. Neurosci. 23, 1992–1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

Cited by

Sorted by citations

Related

Authors
Dodart, J.-C., Marr, R. A., Koistinaho, M., Gregersen, B. M., Malkani, S., Verma, I. M., & Paul, S. M.
Affiliations
Salk Institute for Biological Studies (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-01-18
Volume
102
Issue
4
Pages
1211-1216
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0409072102
PMC
PMC544620
OpenAlex
W2122741223
Cited by
207
References
43
Citations by year
2026: 6 · 2025: 6 · 2024: 11 · 2023: 6 · 2022: 3 · 2021: 7 · 2020: 13 · 2019: 10 · 2018: 13 · 2017: 7 · 2016: 16 · 2015: 2 · 2014: 13 · 2013: 10 · 2012: 10
FWCI
9.63
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, Alzheimer's disease, amyloid-beta, APOE isoforms, APOE ε4, APOE2, lentiviral gene delivery, hippocampus, amyloid burden, neuritic plaques, genetic risk factors
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Hippocampus, Humans, Mice, Transgenic, Genetic Therapy, Lentivirus, Amyloid beta-Peptides, Mice, Apolipoprotein E2

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