The DOI matches its Crossref record; 47 of the 49 references it cites were found in a registry or an index.
Activation of the Amyloid Cascade in Apolipoprotein E4 Transgenic Mice Induces Lysosomal Activation and Neurodegeneration Resulting in Marked Cognitive Deficits
Open accessAbstract
The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor for Alzheimer's disease, is associated histopathologically with elevated levels of brain amyloid. This led to the suggestion that the pathological effects of apoE4 are mediated by cross-talk interactions with amyloid β peptide (Aβ), which accentuate the pathological effects of the amyloid cascade. The mechanisms underlying the Aβ-mediated pathological effects of apoE4 are unknown. We have shown recently that inhibition of the Aβ-degrading enzyme neprilysin in brains of wild-type apoE3 and apoE4 mice results in rapid and similar elevations in their total brain Aβ levels. However, the nucleation and aggregation of Aβ in these mice were markedly affected by the apoE genotype and were specifically enhanced in the apoE4 mice. We presently used the neprilysin inhibition paradigm to analyze the neuropathological and cognitive effects that are induced by apoE4 after activation of the amyloid cascade. This revealed that apoE4 stimulates isoform specifically the degeneration of hippocampal CA1 neurons and of entorhinal and septal neurons, which is accompanied by the accumulation of intracellular Aβ and apoE and with lysosomal activation. Furthermore, these neuropathological effects are associated isoform specifically with the occurrence of pronounced cognitive deficits in the ApoE4 mice. These findings provide the first in vivo evidence regarding the cellular mechanisms underlying the pathological cross talk between apoE4 and Aβ, as well as a novel model system of neurodegeneration in vivo that is uniquely suitable for studying the early stages of the amyloid cascade and the effects thereon of apoE4.
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“Several recent studies provided evidence to support increased content of Ab oligomers in the extracellular space in brains of patients with AD, expressing the human ApoE4 isoform, 37,38 and intraneuronally in mice expressing human ApoE4 isoform after inhibition of Ab-degrading enzyme neprilysin.39”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [39]
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“As shown in another model involving inhibition of the Ab-degrading enzyme neprilysin, intraneuronal oligomerization and accumulation of Ab occurred more readily in mice that expressed the ApoE4 isoform than the ApoE3 isoform.39”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [39]
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1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769
RetractedThe Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
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BackgroundTriple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126
Association of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer's disease
Saunders, A. M., Strittmatter, W. J., Schmechel, D., St. 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 · doi:10.1212/wnl.43.8.1467 · Cited by 3,786
mouse brain in stereotaxic coordinates
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A Century of Alzheimer's Disease
Goedert, M., & Spillantini, M. G. (2006) · Science · doi:10.1126/science.1132814 · Cited by 2,153 · cited 1×
“These include amyloid peptide (A ) and hyperphosphorylated tau, which are the major constituents of senile plaques and neurofibrilary tangles, respectively (Alzheimer et al., 1995; Goedert and Spillantini, 2006; Masters and Beyreuther, 2006), and the allele E4 of apolipoprotein E (apoE4), which is the most prevalent g…”
BackgroundIntracellular amyloid-β in Alzheimer's disease
LaFerla, F. M., Green, K. N., & Oddo, S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2168 · Cited by 1,942
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) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.20.9649 · Cited by 1,525
An english translation of alzheimer’s 1907 paper, “über eine eigenartige erkankung der hirnrinde”
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“Accordingly, in vitro studies revealed that apoE4 binds to A isoform specifically (Strittmatter et al., 1993; LaDu et al., 1994), and that, unlike the AD benign allele apoE3, it does not protect against A -induced toxicity (Puttfarcken et al.”
BackgroundDifferences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease
West, M. J., Coleman, P. D., Flood, D. G., & Troncoso, J. C. (1994) · The Lancet · doi:10.1016/s0140-6736(94)92338-8 · Cited by 1,267
Holtzman, D. M., Bales, K. R., Tenkova, T., Fagan, A. M., Parsadanian, M., Sartorius, L. J., Mackey, B., Olney, J., McKeel, D., Wozniak, D., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050004797 · Cited by 937
A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease
Chen, G., Chen, K. S., Knox, J., Inglis, J., Bernard, A., Martin, S. J., Justice, A., McConlogue, L., Games, D., Freedman, S. B., et al. (2000) · Nature · doi:10.1038/35050103 · Cited by 740
Takahashi, R. H., Milner, T. A., Li, F., Nam, E. E., Edgar, M. A., Yamaguchi, H., Beal, M. F., Xu, H., Greengard, P., & Gouras, G. K. (2002) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64463-x · Cited by 706
Sullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., Quarfordt, S. H., & Maeda, N. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.29.17972 · Cited by 575 · cited 2×
“The two lines of apoE target replacement mice contain chimeric genes consisting of mouse 5 regulatory sequences continuous with mouse exon 1 (noncoding), the 5 half of mouse intron 1 continuous with the 3 half of human intron 1, followed by human exons (and introns) 2– 4 (Sullivan et al., 1997).”
BackgroundMethodIsoform-specific binding of apolipoprotein E to beta-amyloid.
LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S., & Frail, D. E. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31529-6 · Cited by 540
Alzheimer's disease: The amyloid cascade hypothesis: An update and reappraisal
Hardy, J. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-9s317 · Cited by 475 · cited 1×
“This is followed by the formation of distinct A oligomers that induce neuronal impairments and subsequent cell death (Hardy and Selkoe, 2002; Hardy, 2006).”
BackgroundCasas, C., Sergeant, N., Itier, J.-M., Blanchard, V., Wirths, O., van der Kolk, N., Vingtdeux, V., van de Steeg, E., Ret, G., Canton, T., et al. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63388-3 · Cited by 400
Cataldo, A. M., Barnett, J. L., Pieroni, C., & Nixon, R. A. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-16-06142.1997 · Cited by 393
Morris, R., & Frey, U. (1997) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.1997.0136 · Cited by 375 · cited 1×
“This was first assessed by monitoring spatial navigation, which is known to be affected by hippocampal dysfunction (Morris and Frey, 1997), using a dry maze paradigm that monitors the ability of the mice to locate a small water-filled well in an open field (Van der Zee et al.”
Arendt, T., Schindler, C., Brückner, M. K., Eschrich, K., Bigl, V., Zedlick, D., & Marcova, L. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-02-00516.1997 · Cited by 319
Fagan, A. M., Watson, M., Parsadanian, M., Bales, K. R., Paul, S. M., & Holtzman, D. M. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0483 · Cited by 290
Fryer, J. D., Simmons, K., Parsadanian, M., Bales, K. R., Paul, S. M., Sullivan, P. M., & Holtzman, D. M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.5170-04.2005 · Cited by 278
Huang, Y., Weisgraber, K. H., Mucke, L., & Mahley, R. W. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:23:3:189 · Cited by 242
Lysosomal system pathways: Genes to neurodegeneration in Alzheimer's disease
Nixon, R. A., & Cataldo, A. M. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-9s331 · Cited by 222 · cited 1×
“Lysosomal activation Previous studies of AD brains revealed generalized upregulation of the lysosomal system in neurons of affected brain areas (Nixon and Cataldo, 2006), and that apoE4 exacerbates endosomal and lysosomal dysfunction (Cataldo et al.”
BackgroundSpecific Regional Transcription of Apolipoprotein E in Human Brain Neurons
Xu, P., Gilbert, J. R., Qiu, H.-L., Ervin, J. F., Rothrock‐Christian, T., Hulette, C., & Schmechel, D. E. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65305-9 · Cited by 178 · cited 1×
“ApoE is synthesized by glia and neurons (Xu et al., 1999).”
BackgroundJi, Z.-S., Miranda, R. D., Newhouse, Y. M., Weisgraber, K. H., Huang, Y., & Mahley, R. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112109200 · Cited by 177
Fukami, S., Watanabe, K., Iwata, N., Haraoka, J., Lu, B., Gerard, N. P., Gerard, C., Fraser, P., Westaway, D., George-Hyslop, P. S., et al. (2002) · Neuroscience Research · doi:10.1016/s0168-0102(02)00015-9 · Cited by 157 · cited 1×
“Furthermore, because neprilysin levels are particularly elevated in the molecular layer of the DG (Fukami et al., 2002), it is possible that residual neprilysin activity, which remains after thiorphan treatment, can play a role in lowering the levels of A in the DG.”
Levi, O., Jongen‐Rêlo, A. L., Feldon, J., Roses, A. D., & Michaelson, D. M. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(03)00045-7 · Cited by 147 · cited 2×
“The apoE genotype of the mice was confirmed by PCR analysis, as described previously (Levi et al., 2003).”
MethodSelf-citationMasters, C. L., & Beyreuther, K. (2006) · Brain · doi:10.1093/brain/awl251 · Cited by 145
In Vivo Effects of ApoE and Clusterin on Amyloid-β Metabolism and Neuropathology
Holtzman, D. M. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:23:3:247 · Cited by 139
Jordán, J., Galindo, M. F., Miller, R. J., Reardon, C. A., Getz, G. S., & LaDu, M. J. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-01-00195.1998 · Cited by 139
Zerbinatti, C. V., Wahrle, S. E., Kim, H., Cam, J. A., Bales, K., Paul, S. M., Holtzman, D. M., & Bu, G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604436200 · Cited by 129
Reactivity of Apolipoprotein E4 and Amyloid β Peptide
Ji, Z.-S., Müllendorff, K., Cheng, I. H., Miranda, R. D., Huang, Y., & Mahley, R. W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m506646200 · Cited by 127
Hartman, R. E., Laurer, H., Longhi, L., Bales, K. R., Paul, S. M., McIntosh, T. K., & Holtzman, D. M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-23-10083.2002 · Cited by 115 · cited 1×
“, 2005), and it does not seem to be associated with neuritic degeneration and neuronal loss (Holtzman et al., 2000; Hartman et al., 2002), there is a great need for models that reproduce the pathological interactions between apoE4 and A in more detail.”
BackgroundZe, E. A. D. V., Compaan, J. C., de Boer, M., & Luiten, P. (1992) · Journal of Neuroscience · doi:10.1523/jneurosci.12-12-04808.1992 · Cited by 110
Dolev, I., & Michaelson, D. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404458101 · Cited by 102
Self-citationAccelerated hippocampal atrophy in Alzheimer's disease with apolipoprotein E ε4 allele
Mori, E., Lee, K., Yasuda, M., Hashimoto, M., Kazui, H., Hirono, N., & Matsui, M. (2002) · Annals of Neurology · doi:10.1002/ana.10093 · Cited by 91
Matsumori, Y., Hong, S. M., Fan, Y., Kayama, T., Hsu, C. Y., Weinstein, P. R., & Liu, J. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.10.015 · Cited by 87 · cited 1×
“The free-floating sections were immunostained as described previously (Matsumori et al., 2006), with the following primary antibodies (Abs): biotinylated anti-A monoclonal Ab (mAb) 4G8 (1:200; Signet, Dedham, MA); rabbit anti-A 42 (1:500; Chemicon, Temecula, CA); rabbit anti-A 40 (1:500; Chemicon); goat anti-apoE (1:5…”
BackgroundRoses, A. D. (2006) · Journal of Alzheimer's Disease · doi:10.3233/jad-2006-9s340 · Cited by 86
Puttfarcken, P. S., Manelli, A. M., Falduto, M. T., Getz, G. S., & LaDu, M. J. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.68020760.x · Cited by 79
Amyloid β-Peptide: The Inside Story
Tseng, B., Kitazawa, M., & LaFerla, F. (2004) · Current Alzheimer Research · doi:10.2174/1567205043332045 · Cited by 72
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γ-Secretase Cleavage Site Specificity Differs for Intracellular and Secretory Amyloid β
Grimm, H. S., Beher, D., Lichtenthaler, S. F., Shearman, M. S., Beyreuther, K. T., & Hartmann, T. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m210380200 · Cited by 40
Role of apoE/Aβ interactions in Alzheimer's disease: insights from transgenic mouse models
Brendza, R. P., Bales, K. R., Paul, S. M., & Holtzman, D. M. (2002) · Molecular Psychiatry · doi:10.1038/sj.mp.4001006 · Cited by 30
The nucleation growth and reversibility of Amyloid-β deposition in vivo
Dolev, I., & Michaelson, D. M. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-102-313 · Cited by 13
Self-citation
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Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168
“Recently, APOE4 and Aβ aggregates (the aggregation of which was induced by inhibiting neprilysin) were found to act synergistically to induce neurodegeneration in the mouse brai”
BackgroundAutophagy failure in Alzheimer's disease—locating the primary defect
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ApoE4: an emerging therapeutic target for Alzheimer’s disease
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Self-citation
Metadata
- Authors
- Belinson, H., Lev, D., Masliah, E., & Michaelson, D. M.
- Affiliations
- Tel Aviv University (IL)
- University of California San Diego (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-04-30
- Volume
- 28
- Issue
- 18
- Pages
- 4690-4701
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3844816
- OpenAlex
- W2085235587
- Cited by
- 101
- References
- 49
- Citations by year
- 2025: 3 · 2024: 7 · 2023: 1 · 2022: 8 · 2021: 4 · 2020: 5 · 2019: 5 · 2018: 6 · 2017: 2 · 2016: 10 · 2015: 3 · 2014: 3 · 2013: 9 · 2012: 10
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG‐022074, AG10435)
- National Institute on Aging (P01AG010435, AG022074, P01AG022074, AG48440, AG10435)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, amyloid hypothesis, amyloid-beta, neprilysin inhibition, lysosomal activation, neurodegeneration, cognitive impairment, CA1 pyramidal neurons, entorhinal cortex, septal neurons, amyloid-beta aggregation, Alzheimer's disease, transgenic mice
- MeSH terms
- Analysis of Variance, Animals, Cognition Disorders, Disease Models, Animal, Exploratory Behavior, Hippocampus, Learning, Lysosomes, Mice, Inbred C57BL, Mice, Transgenic, Neuropsychological Tests, Synapses, Water Deprivation, Neprilysin, Amyloid beta-Peptides, Drug Delivery Systems, Neurodegenerative Diseases, Microscopy, Electron, Transmission, Mice, Apolipoprotein E3, Apolipoprotein E4
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