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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]
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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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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×
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Background
Research works printed but not linked: 1
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Cited by
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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
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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).”
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Neurotoxicity of Amyloid -Protein: Synaptic and Network Dysfunction
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Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers
Lacor, P. N., Buniel, M. C., Chang, L., Fernandez, S. J., Gong, Y., Viola, K. L., Lambert, M. P., Velasco, P. T., Bigio, E. H., Finch, C. E., et al. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.3432-04.2004 · Cited by 954
“Such impairment of synaptic plasticity may account for plaque-independent cognitive failures seen in hAPP transgenic mice (Hsia et al., 1999; Mucke et al., 2000; Buttini et al., 2002; Van Dam et al., 2003), which accumulate oligomers in an age-, region-, and transgenedependent manner (Chang et al.”
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Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases
Huang, Y., & Mahley, R. W. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.025 · Cited by 829
ApoE genotype accounts for the vast majority of AD risk and AD pathology
Raber, J., Huang, Y., & Ashford, J. W. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.12.023 · Cited by 599
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BackgroundXu, Q., Bernardo, A., Walker, D., Kanegawa, T., Mahley, R. W., & Huang, Y. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.5476-05.2006 · Cited by 524
“, 2002), neurodegeneration (Buttini et al., 1999; Buttini et al., 2002), androgen receptor deficiency (Raber et al.”
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Duyckaerts, C., Potier, M.-C., & Delatour, B. (2008) · Acta Neuropathologica · doi:10.1007/s00401-007-0312-8 · Cited by 375
“This effect was prevented by the expression of the ApoE3 allele [41].”
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“The dependence of apoE4 fragmentation on the production of apoE in neurons might also explain why NSE-apoE4 mice are susceptible to age-related neurodegeneration (Buttini et al., 1999, 2002), whereas GFAP-apoE4 mice are not (Hartman et al., 2001).”
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Kivipelto, M., Rovio, S., Ngandu, T., Kåreholt, I., Eskelinen, M. H., Winblad, B. G., Hachinski, V., Cedazo-Mı́nguez, Á., Soininen, H. S., Tuomilehto, J., et al. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00296.x · Cited by 359
RAGE potentiates Aβ‐induced perturbation of neuronal function in transgenic mice
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“…independently of pathological aggregation of disease-associated proteins (Lambert et al., 1998; Santacruz et al., 2005; Yamamoto et al., 2000), and they can result from synaptic dysfunction rather than neuronal loss (Buttini et al., 2002; Mucke et al., 2000; Walsh et al., 2002; Wang et al., 2002).”
APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease
Youmans, K. L., Tai, L. M., Nwabuisi-Heath, E., Jungbauer, L., Kanekiyo, T., Gan, M., Kim, J., Eimer, W. A., Estus, S., Rebeck, G. W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.407957 · Cited by 268
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“In several lines of mutant APP transgenic mice, structural changes in presynaptic terminals or neuronal loss are correlated with an increase in A concentration in the brain, but not with plaque load (Hsia et al., 1999; Mucke et al., 2000; Buttini et al., 2002).”
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Dendrite and dendritic spine alterations in alzheimer models
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“…deficits (12–15 mo) preceded plaque formation (19–24 mo), and despite Journal of Molecular Neuroscience Volume 23, 2004 their marked difference in plaque loads (>10-fold), old hAPP/apoE4 and hAPP/apoE3 bigenic mice (19–24 mo) had comparable synaptic and cholinergic deficits (Buttini et al., 2002).”
BackgroundInfluentialMalm, T. M., Koistinaho, M., Pärepalo, M., Vatanen, T., Ooka, A., Karlsson, S., & Koistinaho, J. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.09.009 · Cited by 301
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Martins, I. J., Berger, T. R., Sharman, M. J., Verdile, G., Fuller, S. J., & Martins, R. N. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06408.x · Cited by 237
“…differences in brain function have been found in other areas, for example, apoE4 has been found to be less protective against oxidative stress, to affect signaling pathways, and to result in greater cholinergic dysfunction in AD (Buttini et al. 2002; for a review see Cedazo-Minguez 2007).”
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Zhao, J., Davis, M. D., Martens, Y. A., Shinohara, M., Graff-Radford, N. R., Younkin, S. G., Wszolek, Z. K., Kanekiyo, T., & Bu, G. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx155 · Cited by 221
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Nakase, T., & Naus, C. C. G. (2004) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2004.01.009 · Cited by 206
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“In transgenic (TG) mice overexpressing hAPP/A in neurons, synaptic and behavioral deficits are detectable well before plaque formation (Holcomb et al., 1999; Hsia et al., 1999; Mucke et al., 2000; Raber et al., 2000; Buttini et al., 2002; Westerman et al., 2002; Palop et al., 2003).”
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Tzioras, M., Davies, C., Newman, A., Jackson, R., & Spires‐Jones, T. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12529 · Cited by 147
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“Journal compilation © 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd A , and the age of the animal, but not on plaque deposition [75].”
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“…(Price et al. 1998, Link 2001) have been developed such as: APP transgenic mice (Masliah et al. 1996), ApoE transgenic mice (Buttini et al. 1999, Raber et al., 2000a) and C elegans (Link et al. 2003), tauopathy Drosophila (Wittmann et al. 2001), and also APP þ ApoE mice (Buttini et al. 2002).”
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“It is known that A induces not only synaptic disruption but also cholinergic deficits in a mice model of AD [57].”
APOE4 is associated with greater atrophy of the hippocampal formation in Alzheimer's disease
Pievani, M., Galluzzi, S., Thompson, P. M., Rasser, P. E., Bonetti, M., & Frisoni, G. B. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2010.12.081 · Cited by 134
“More specifically, cell and animal models have observed this detrimental effect in the hippocampus (Holtzman et al., 2000; Buttini et al., 2002; Schmechel et al., 1993; Brecht et al., 2004; Harris et al., 2003; Tesseur et al., 2000).”
BackgroundApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation
Sen, A., Nelson, T. J., & Alkon, D. L. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.0260-15.2015 · Cited by 133
p21-activated Kinase-aberrant Activation and Translocation in Alzheimer Disease Pathogenesis
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Intron-3 Retention/Splicing Controls Neuronal Expression of Apolipoprotein E in the CNS
Xu, Q., Walker, D., Bernardo, A., Brodbeck, J., Balestra, M. E., & Huang, Y. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3253-07.2008 · Cited by 122
“…lysosomal leakage, neurodegeneration, androgen receptor deficiency, and cognitive decline (Tolar et al., 1997, 1999; Raber et al., 1998, 2002; Buttini et al., 1999, 2002; Tesseur et al., 2000; Huang et al., 2001; Ji et al., 2002; Harris et al., 2003, 2004a; Brecht et al., 2004; Chang et al.,…”
BackgroundApolipoprotein E and Alzheimer disease
Huang, Y. (2006) · Neurology · doi:10.1212/01.wnl.0000192102.41141.9e · Cited by 105
Metabolism of amyloid β peptide and pathogenesis of Alzheimer's disease
Saido, T. C., & Iwata, N. (2006) · Neuroscience Research · doi:10.1016/j.neures.2005.12.015 · Cited by 102
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Cholinergic forebrain degeneration in the APPswe/PS1ΔE9 transgenic mouse
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“It is interesting to note that the majority of studies reporting cholinergic pathologies were performed in single APP or PS1 mutant mice, which have limited or no Aβ deposition (Hernandez et al., 2001; Jaffar et al., 2001; Boncristiano et al., 2002; Buttini et al., 2002; German et al., 2003; Aucoin et al., 2005; Bales…”
BackgroundInfluentialEFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerʼns disease
Tai, L. M., Balu, D., Avila-Munoz, E., Abdullah, L., Thomas, R., Collins, N., Valencia-Olvera, A. C., & LaDu, M. J. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r076315 · Cited by 93
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“ApoE4 is associated with progressive synaptic deficits in both AD patients and hAPOE-Tg mouse models [83-87].”
BackgroundHuang, T. L. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-090934 · Cited by 91
“synapses [100], and show increased deficits in learn-”
BackgroundProteomic Analysis of Maternal Serum in Down Syndrome: Identification of Novel Protein Biomarkers
Nagalla, S. R., Canick, J. A., Jacob, T., Schneider, K. A., Reddy, A. P., Thomas, A., Dasari, S., Lu, X., Lapidus, J., Lambert-Messerlian, G. M., et al. (2007) · Journal of Proteome Research · doi:10.1021/pr060539h · Cited by 90
Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation
Nilsson, L. N. G., Arendash, G. W., Leighty, R. E., Costa, D. A., Low, M. A., Garcia, M. F., Cracciolo, J. R., Rojiani, A. M., Wu, X., Bales, K. R., et al. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.12.011 · Cited by 88
“Particularly interesting is the finding that ApoE4 is less neuroprotective than ApoE3 both in vitro and in vivo [9].”
BackgroundThe benefit of docosahexaenoic acid for the adult brain in aging and dementia
Salem, N., Vandal, M., & Calon, F. (2014) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2014.10.003 · Cited by 86
Synaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms
Forero, D. A., Casadesús, G., Perry, G. L., & Arboleda, H. (2006) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2006.tb00439.x · Cited by 89
Brodbeck, J., Balestra, M. E., Saunders, A. M., Roses, A. D., Mahley, R. W., & Huang, Y. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709906104 · Cited by 86
ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-β1–42
Trommer, B. L., Shah, C., Yun, S. H., Gamkrelidze, G., Pasternak, E. S., Blaine Stine, W., Manelli, A., Sullivan, P., Pasternak, J. F., & LaDu, M. J. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.08.011 · Cited by 82
“have also shown that when these mice are crossed with NSE-apoE mice, apoE3 but not apoE4 delays age- and Ah-dependent synaptic and cholinergic deficits and that the mechanism is independent of plaque deposition (Buttini et al., 2002).”
Mahley, R. W., & Huang, Y. (2006) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.2006.00679.x · Cited by 84
Mechanisms linking apolipoprotein E isoforms with cardiovascular and neurological diseases.
Huang, Y. (2010) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32833af368 · Cited by 82
Self-citationCholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice
Perez, S. E., He, B., Muhammad, N., Oh, K.-J., Fahnestock, M., Ikonomovic, M. D., & Mufson, E. J. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.10.002 · Cited by 80
Xu, Q., Brecht, W. J., Weisgraber, K. H., Mahley, R. W., & Huang, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311256200 · Cited by 80
Buttini, M., Masliah, E., Yu, G.-Q., Palop, J. J., Chang, S., Bernardo, A., Lin, C., Wyss-Coray, T., Huang, Y., & Mucke, L. (2010) · The American Journal of Pathology · doi:10.2353/ajpath.2010.090973 · Cited by 80
Greasing the wheels of Aβ clearance in Alzheimer's Disease: The role of lipids and apolipoprotein E
Fan, J., Donkin, J., & Wellington, C. (2009) · BioFactors · doi:10.1002/biof.37 · Cited by 97
Raffaı̈, R. L., & Weisgraber, K. H. (2003) · Journal of Lipid Research · doi:10.1194/jlr.r300007-jlr200 · Cited by 76
“of human APP display a loss of synaptic density and behavioral phenotypes before amyloid plaques appear in the brain (14-16).”
BackgroundBehavioral and neurobiological markers of Alzheimer’s disease in Ts65Dn mice: effects of estrogen
Hunter, C. L., Bimonte‐Nelson, H. A., Nelson, M., Eckman, C. B., & Granholm, A. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.10.010 · Cited by 77
Mapping the effect of APOE ε4 on gray matter loss in Alzheimer's disease in vivo
Pievani, M., Rasser, P. E., Galluzzi, S., Benussi, L., Ghidoni, R., Sabattoli, F., Bonetti, M., Binetti, G. G., Thompson, P. M., & Frisoni, G. B. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.01.009 · Cited by 71
“Furthermore, the ε4 allele in the temporal lobe has been associated with impaired synaptic activity (Buttini et al., 2002), reduced neurite outgrowth (Sun et al., 1998), more severe Abeta deposition (Tiraboschi et al., 2004; Nagy et al., 1995) and cholinergic deficits (Buttini et al., 2002).”
BackgroundResultInfluentialKatsouri, L., & Georgopoulos, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021880 · Cited by 72
“deficient for ApoE show a dramatic decrease in fibrillary amyloid deposits [5,6,7,8,9].”
BackgroundBien-Ly, N., Andrews-Zwilling, Y., Xu, Q., Bernardo, A., Wang, C., & Huang, Y. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1018381108 · Cited by 71
Mallucci, G. R. (2009) · Prion · doi:10.4161/pri.3.4.9981 · Cited by 66
Gruart, A., López, J. C., Muñoz, M.-D., & Delgado-Garcia, J. M. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2008.03.001 · Cited by 67
Klein, R. C., Mace, B. E., Moore, S. D., & Sullivan, P. M. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.10.027 · Cited by 67
“plaques and tangles) (Buttini et al., 2002) (Mucke et al.”
Spampinato, M. V., Rumboldt, Z., Hosker, R. J., Mintzer, J. E., & Initiative, A. D. N. (2010) · Radiology · doi:10.1148/radiol.10100307 · Cited by 68
Han, S.-H., Park, J.-C., & Mook-Jung, I. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.12.004 · Cited by 67
Roberson, E. D., & Kao, A. W. (2009) · Cambridge University Press eBooks · doi:10.1017/cbo9780511581410.010 · Cited by 67
Aucoin, J.-S., Jiang, P., Aznavour, N., Tong, X.-K., Buttini, M., Descarries, L., & Hamel, E. (2005) · Neuroscience · doi:10.1016/j.neuroscience.2004.11.047 · Cited by 66
Aβ, tau and ApoE4 in Alzheimer's disease: the axonal connection
Adalbert, R., Gilley, J., & Coleman, M. P. (2007) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.02.004 · Cited by 65
Wang, Z., Liu, Q., Zhang, R., Liu, S., Xia, Z., & Hu, Y. G. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.07.041 · Cited by 66
Poirier, R., Wolfer, D. P., Welzl, H., Tracy, J., Galsworthy, M. J., Nitsch, R. M., & Mohajeri, M. H. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.08.003 · Cited by 64
Mannix, R. C., Zhang, J., Park, J., Zhang, X., Bilal, K., Walker, K., Tanzi, R. E., Tesco, G., & Whalen, M. J. (2011) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2010.99 · Cited by 62
“…2001), and APOE4 is associated with age-related decreases in synaptophysin-immunoreactive presynaptic terminals, decreased choline acetyltransferase activity, and reduced cholinergic fibers in mutant hAPP mice expressing APOE4 under the direction of neuron-specific enolase (Buttini et al, 2002).”
BackgroundContestabile, A., Ciani, E., & Contestabile, A. (2007) · Neurochemical Research · doi:10.1007/s11064-007-9497-4 · Cited by 64
Hirsch-Reinshagen, V., & Wellington, C. L. (2007) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32813aeabf · Cited by 61
ApoE isoforms differentially regulates cleavage and secretion of BDNF
Sen, A., Nelson, T. J., & Alkon, D. L. (2017) · Molecular Brain · doi:10.1186/s13041-017-0301-3 · Cited by 60
Stefani, A., Martorana, A., Bernardini, S., Panella, M., Mercati, F., Orlacchio, A., & Pierantozzi, M. (2006) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2006.09.014 · Cited by 58
“These findings are consistent with a sequence of pathologic events whereby amyloid deposit comes prior to tangles in the sequence linking the apolipoprotein E ε4 allele to level of cognition [31,32].”
ResultWhy lipids are important for Alzheimer disease?
Hirsch-Reinshagen, V., Burgess, B. L., & Wellington, C. L. (2009) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-008-0012-2 · Cited by 86
“Finally, replacement of murine apoE with human apoE2, E3, and E4 leads to isoform-specific differences in amyloid load, with apoE4expressing mice developing the greatest amyloid load and apoE2-expressing mice developing the least [28–31], consistent with the apoE isoform effect on vascular and parenchymal Ab deposits…”
BackgroundLoreth, D., Ozmen, L., Revel, F. G., Knoflach, F., Wetzel, P., Frotscher, M., Metzger, F., & Kretz, O. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.03.011 · Cited by 58
“Thus, evidence based on some AD animal models suggests that any potential deficits within the cholinergic system do not make a primary contribution to the pathophysiology of AD (Buttini et al., 2002; Contestabile et al., 2008; German et al., 2003).”
BackgroundKaushal, N., Ramesh, V., & Gozal, D. (2012) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00025.2012 · Cited by 55
“Many AD-like features have been reproduced in murine models expressing human ApoE4, including increased plaques (24, 25), reduced presynaptic terminals with ApoE4 (4, 5, 6), increased phosphorylated tau with neuronal expression of ApoE4 (3, 21, 59), and impaired spatial learning and memory (28, 42, 43).”
BackgroundIntroducing Human APOE into A β Transgenic Mouse Models
Tai, L. M., Youmans, K. L., Jungbauer, L., Yu, C., & LaDu, M. J. (2011) · International Journal of Alzheimer’s Disease · doi:10.4061/2011/810981 · Cited by 52
del Toro, E. D., Moreno, A. R., Porras‐García, E., Sánchez‐Campusano, R., Blanchard, V., Laville, M., Böhme, G. A., Bénavidès, J., & Delgado‐García, J. M. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03643.x · Cited by 52
“…suggests that functional alterations could occur before senile plaque formation, a proposition already sustained by others from molecular, cellular and ⁄ or functional studies (Moechars et al., 1999; Wong et al., 1999; Buttini et al., 2002; Selkoe, 2002; Terwel et al., 2002; Van Dam et al., 2003).”
BackgroundResultInfluentialBoncristiano, S., Calhoun, M. E., Howard, V., Bondolfi, L., Kaeser, S. A., Wiederhold, K.-H., Staufenbiel, M., & Jucker, M. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.06.010 · Cited by 68
“Studies in transgenic mice are conflicting, with some reporting a loss of synapses, while others found no change [4,11,12,14,18,27].”
BackgroundResultInfluentialRózga, M., & Bal, W. (2009) · Chemical Research in Toxicology · doi:10.1021/tx900358j · Cited by 54
Kou, X., Chen, D., & Chen, N. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20071591 · Cited by 52
Key Peptides and Proteins in Alzheimer’s Disease
Penke, B., Bogár, F., Paragi, G., Gera, J., & Fülöp, L. (2019) · Current Protein and Peptide Science · doi:10.2174/1389203720666190103123434 · Cited by 51
Age and ApoE genotype interaction in Alzheimer's disease: an FDG-PET study
Mosconi, L., Sorbi, S., Nacmias, B., Cristofaro, M. T. D., Fayyaz, M., Bracco, L., Herholz, K., & Pupi, A. (2004) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2003.12.005 · Cited by 50
Huang, Y. (2011) · Biochemical Society Transactions · doi:10.1042/bst0390924 · Cited by 53
The potential role of nutritional components in the management of Alzheimer's Disease
van der Beek, E. M., & Kamphuis, P. J. G. H. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.01.049 · Cited by 47
Mouse models of Alzheimer's disease: The long and filamentous road
Phinney, A. L., Horne, P., Yang, J., Janus, C., Bergeron, C., & Westaway, D. A. (2003) · Neurological Research · doi:10.1179/016164103101202020 · Cited by 47
Yuan, Y., Zhang, Z., Bai, F., You, J., Yu, H., Shi, Y., & Liu, W. (2009) · Journal of Affective Disorders · doi:10.1016/j.jad.2009.07.003 · Cited by 45
Androgens, ApoE, and Alzheimer's Disease
Raber, J. (2004) · Science of Aging Knowledge Environment · doi:10.1126/sageke.2004.11.re2 · Cited by 48
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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