The DOI matches its Crossref record; 112 of the 112 references it cites were found in a registry or an index.
Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid β peptides but not on plaque formation
Open accessAbstract
The most frequent human apolipoprotein (apo) E isoforms, E3 and E4, differentially affect Alzheimer's disease (AD) risk (E4 > E3) and age of onset (E4 < E3). Compared with apoE3, apoE4 promotes the cerebral deposition of amyloid beta (Abeta) peptides, which are derived from the amyloid precursor protein (APP) and play a central role in AD. However, it is uncertain whether Abeta deposition into plaques is the main mechanism by which apoE isoforms affect AD. We analyzed murine apoE-deficient transgenic mice expressing in their brains human APP (hAPP) and Abeta together with apoE3 or apoE4. Because cognitive decline in AD correlates better with decreases in synaptophysin-immunoreactive presynaptic terminals, choline acetyltransferase (ChAT) activity, and ChAT-positive fibers than with plaque load, we compared these parameters in hAPP/apoE3 and hAPP/apoE4 mice and singly transgenic controls at 6-7, 12-15, and 19-24 months of age. Brain aging in the context of high levels of nondeposited human Abeta resulted in progressive synaptic/cholinergic deficits. ApoE3 delayed the synaptic deficits until old age, whereas apoE4 was not protective at any of the ages analyzed. Old hAPP/apoE4 mice had more plaques than old hAPP/apoE3 mice, but synaptic/cholinergic deficits preceded plaque formation in hAPP/apoE4 mice. Moreover, despite their different plaque loads, old hAPP/apoE4 and hAPP/apoE3 mice had comparable synaptic/cholinergic deficits, and these deficits were found not only in the hippocampus but also in the neocortex, which in most mice contained no plaques. Thus, apoE3, but not apoE4, delays age- and Abeta-dependent synaptic deficits through a plaque-independent mechanism. This difference could contribute to the differential effects of apoE isoforms on the risk and onset of AD.
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“Introduction of human APOE to existing FAD-Tg mice significantly delays plaque deposition, although once detected, plaque levels are generally greater with APOE4 than APOE3 (3, 6 -8).”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [6]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“ApoE has a major impact on the generation of amyloid deposits in the AD mouse brain and deletion of ApoE in most AD mouse models significantly inhibits amyloid plaque formation [6], [7], [8].”
From Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model (2011) · cites this paper as [6]
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“Other studies using transgenic mice that possess different human apoE transgenes also demonstrate an isoform-specific difference (E4>E3) in Aβ deposition (Buttini et al., 2002; Dolev and Michaelson, 2004).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Buttini et al., 2002
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“APP transgenic mice deficient for ApoE show a dramatic decrease in fibrillary amyloid deposits [5], [6], [7], [8], [9].”
From Lack of LDL receptor enhances amyloid deposition and decreases glial response in an Alzheimer's disease mouse model (2011) · cites this paper as [6]
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Cites
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
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“Because synaptic deficits correlate well with the development of cognitive deficits in AD (DeKosky and Scheff, 1990; Terry et al., 1991; Langlais et al., 1993; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998), the differential effects of apoE3 and apoE4 identified here might relate closely to the effects of…”
BackgroundInfluentialAlzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063 · cited 3×
“These associations have widely been interpreted as evidence that apoE4 increases AD risk through its effect on amyloid deposition (Holtzman et al., 2000a,b; Selkoe, 2001).”
BackgroundTerry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991) · Annals of Neurology · doi:10.1002/ana.410300410 · Cited by 4,397 · cited 2×
“We focused our analysis on SYN-IR presynaptic terminals, choline acetyltransferase (ChAT) activity, and cholinergic fibers, because decreases in these parameters correlate well with cognitive decline in AD (Terry et al., 1991; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998).”
BackgroundDiffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · cited 1×
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BackgroundAlzheimer-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 · cited 2×
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DeKosky, S. T., & Scheff, S. W. (1990) · Annals of Neurology · doi:10.1002/ana.410270502 · Cited by 2,376 · cited 2×
“Because synaptic deficits correlate well with the development of cognitive deficits in AD ( DeKosky and Scheff, 1990; Terry et al., 1991; Langlais et al., 1993; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998), the differential effects of apoE3 and apoE4 identified here might relate closely to the effects of…”
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“Its activity is 40–90% lower in AD brains than in control brains, and this reduction correlates with cognitive decline (Perry et al., 1978; Davies, 1979; Wilcock et al., 1982; Sims et al., 1983; Neary et al., 1986; Bierer et al., 1995; Samuel et al., 1997; Cummings, 2000).”
BackgroundMucke, L., Masliah, E., Yu, G.-Q., Mallory, M., Rockenstein, E. M., Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K., & McConlogue, L. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-11-04050.2000 · Cited by 1,856 · cited 12×
“…terminals in hAPP mice expressing high levels of soluble human A On the murine apoE wild-type background, hAPP mice develop an age-dependent loss of SYN-IR presynaptic terminals that is associated with major deficits in synaptic transmission strength (Hsia et al., 1999; Mucke et al., 2000).”
BackgroundInfluentialCNS synaptogenesis promoted by glia-derived cholesterol
Mauch, D. H., Nägler, K., Schumacher, S., Göritz, C., Müller, E.-C., Otto, A., & Pfrieger, F. W. (2001) · Science · doi:10.1126/science.294.5545.1354 · Cited by 1,711 · cited 1×
“…and A -dependent synaptic deficits include promotion of neurite extension (Nathan et al., 1994; Holtzman and Fagan, 1998) and synapse formation (Mauch et al., 2001), stabilization of microtubules (Strittmatter et al., 1994; Nathan et al., 1995) and endosomal–lysosomal membranes (Ji et al.,…”
Background
Research works printed but not linked: 1
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Cited by
Sorted by citations
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459
Alzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758
Self-citationThe role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
“Other studies using transgenic mice that possess different human apoE transgenes also demonstrate an isoform-specific difference (E4>E3) in Aβ deposition (Buttini et al., 2002; Dolev and Michaelson, 2004).”
BackgroundPickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P. A., Small, S., Spencer, B., Rockenstein, E., Levine, B., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33585 · Cited by 268
Neurotoxicity of Amyloid -Protein: Synaptic and Network Dysfunction
Mucke, L., & Selkoe, D. J. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006338 · Cited by 1,000
Metadata
- Authors
- Buttini, M., Yu, G.-Q., Shockley, K., Huang, Y., Jones, B., Masliah, E., Mallory, M., Yeo, T., Longo, F. M., & Mucke, L.
- Affiliations
- Gladstone Institutes (US)
- University of California San Diego (US)
- San Francisco VA Medical Center (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-12-15
- Volume
- 22
- Issue
- 24
- Pages
- 10539-10548
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758409
- OpenAlex
- W2100295360
- Cited by
- 183
- References
- 112
- Citations by year
- 2025: 5 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 8 · 2019: 6 · 2018: 4 · 2017: 5 · 2016: 2 · 2015: 9 · 2014: 2 · 2013: 9 · 2012: 9
- FWCI
- 8.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- Locations
- Journal of Neuroscience (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health (AG11385)
- National Institute on Aging (AG-11385, R37AG011385, R01AG011385)
- National Cancer Institute (R01CA094141)
- National Institute of Neurological Disorders and Stroke (NS41787, R01NS041787)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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, APOE ε4, APOE3, Alzheimer's disease, amyloid-beta, amyloid plaques, synaptic deficits, cholinergic deficit, choline acetyltransferase, synaptophysin, brain aging, amyloid precursor protein, transgenic mice, hippocampus, neocortex
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Choline O-Acetyltransferase, Cholinergic Fibers, Humans, Immunohistochemistry, Mice, Transgenic, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Synaptophysin, Presynaptic Terminals, Protein Isoforms, Mice, Apolipoprotein E3, Apolipoprotein E4
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