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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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Cited by
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Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
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
Nixon, R. A., & Yang, D.-S. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.01.021 · Cited by 595
Colacurcio, D. J., & Nixon, R. A. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.05.004 · Cited by 548
How does diabetes accelerate Alzheimer disease pathology?
Sims-Robinson, C., Kim, B., Rosko, A., & Feldman, E. L. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2010.130 · Cited by 492
ApoE4: an emerging therapeutic target for Alzheimer’s disease
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Self-citationYang, D.-S., Stavrides, P., Mohan, P. S., Kaushik, S., Kumar, A., Ohno, M., Schmidt, S. D., Wesson, D., Bandyopadhyay, U., Jiang, Y., et al. (2011) · Brain · doi:10.1093/brain/awq341 · Cited by 429
“Ab immunoreactivity has been previously detected by immunocytochemistry in early endosomes, late endosome/multivesicular bodies and autophagic vacuoles in the brains of Alzheimer’s disease and Alzheimer’s disease mouse models (Takahashi et al., 2002; Cataldo et al., 2004a; Yu et al., 2005; Belinson et al., 2008).”
BackgroundNixon, R. A. (2017) · The FASEB Journal · doi:10.1096/fj.201700359 · Cited by 400
Autophagy and Alzheimer’s Disease
Li, Q., Liu, Y., & Sun, M. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-016-0386-8 · Cited by 337
“Studies from ApoE4 transgenic mice showed that overexpression of ApoE4 elevated Ab42 amount in lysosome and finally led to hippocampus neurons death (Belinson et al. 2008).”
BackgroundRecent advances in our understanding of neurodegeneration
Jellinger, K. A. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0240-y · Cited by 274
“ApoE4 and Ab aggregates were found to act synergistically to induce neurodegeneration in the mouse brain (Belinson et al. 2008), whereas Ab accumulation induced by mutant APP did not (Muller et al.”
BackgroundThe biological pathways of Alzheimer disease: a review
Calabrò, M., Rinaldi, C., Santoro, G., & Crisafulli, C. (2020) · AIMS neuroscience · doi:10.3934/neuroscience.2021005 · Cited by 287
“For example, Apolipoprotein E4 (apoE4) overexpression potentially causes an Aβ accumulation in lysosomes, leading to neuronal death in the hippocampus [299,300].”
BackgroundIncreased Accumulation of Intraneuronal Amyloid β in HIV-Infected Patients
HNRC, Achim, C. L., Adame, A., Dumaop, W., Everall, I. P., & Masliah, E. (2009) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-009-9152-8 · Cited by 205
“Double immunolabeling and confocal laser microscopy To evaluate the co-localization between Aβ immunoreactivity and lysosomal markers, double immunocytochemical analysis was performed (Belinson et al. 2008).”
Self-citationThe Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease
Ihara, Y., Morishima-Kawashima, M., & Nixon, R. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006361 · Cited by 190
“Expression of the ApoE 14 allele, but not ApoE 13, in mice administered a neprilysin inhibitor increases Ab immunoreactivity in lysosomes and causes neurodegeneration of hippocampal CA1, entorhinal, and septal neurons (Belinson et al. 2008).”
BackgroundAutophagy and Neuronal Cell Death in Neurological DisordersPreprint
Nixon, R. A., & Yang, D.-S. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008839 · Cited by 183
“The expression of ApoE4, but not the ApoE3 allele, increases levels of intracellular Ab peptide (Ab), enlarges lysosomes and alters their morphology in a mouse AD model, and causes neurodegeneration of neurons typically vulnerable in AD (Belinson et al. 2008).”
BackgroundHOOK, V. Y. H., Yoon, M. C., Mosier, C., Ito, G., Podvin, S., Head, B. P., Rissman, R. A., O’Donoghue, A. J., & Hook, G. (2020) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2020.140428 · Cited by 177
Sato, N., & Morishita, R. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00199 · Cited by 167
“Finally, activation of Aβ cascade in ApoEε4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits (Belinson et al., 2008).”
BackgroundTargeting Autophagy for the Treatment of Alzheimer’s Disease: Challenges and Opportunities
Liu, J., & Li, L. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00203 · Cited by 162
“finally led to neuronal death in the hippocampus (Belinson et al., 2008).”
BackgroundTzioras, M., Davies, C., Newman, A., Jackson, R., & Spires‐Jones, T. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12529 · Cited by 147
Garai, K., Verghese, P. B., Baban, B., Holtzman, D. M., & Frieden, C. (2014) · Biochemistry · doi:10.1021/bi5008172 · Cited by 145
Advances in the pathogenesis of Alzheimer’s disease: a re-evaluation of amyloid cascade hypothesis
Dong, S., Duan, Y., Hu, Y., & Zhao, Z. (2012) · Translational Neurodegeneration · doi:10.1186/2047-9158-1-18 · Cited by 147
“In fact, it has been reported that activation of the amyloid cascade may isoform-specifically induce lysosomal activation and neurodegeneration of hippocampal CA1, entorhinal and septal neurons, which are responsible for the marked cognitive deficits in apolipoprotein transgenic mice [77].”
BackgroundReversal of apoE4-driven brain pathology and behavioral deficits by bexarotene
Boehm-Cagan, A., & Michaelson, D. M. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.5198-13.2014 · Cited by 134
“For SDSelectrophoresis, the samples were boiled for 10 min with 0.5% SDS and immunoblotted as described previously (Belinson et al., 2008; Haas et al., 2012).”
MethodInfluentialSelf-citationImpaired Autophagy in APOE4 Astrocytes
Simonovitch, S., Schmukler, E., Bespalko, A., Iram, T., Frenkel, D., Holtzman, D. M., Masliah, E., Michaelson, D. M., & Pinkas-Kramarski, R. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-151101 · Cited by 136
Self-citationTampellini, D., Rahman, N., Gallo, E. F., Huang, Z., Dumont, M., Capetillo-Zarate, E., Ma, T., Zheng, R., Lu, B., Nanus, D. M., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2292-09.2009 · Cited by 127
“, 2001), but when thiorphan was infused into the brain, only total levels of A 42 but not A 40 were elevated (Iwata et al., 2000; Belinson et al., 2008).”
BackgroundAccumulation of intraneuronal Aβ correlates with ApoE4 genotype
Christensen, D. Z., Schneider-Axmann, T., Lucassen, P. J., Bayer, T. A., & Wirths, O. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0666-1 · Cited by 120
“Furthermore, inhibition of the Ab-degrading enzyme neprilysin in ApoE3 and ApoE4 mice results in an ApoE4 isoform-specific degeneration of hippocampal CA1 neurons, which is accompanied by intracellular accumulation of Ab and ApoE and lysosomal activation [6].”
BackgroundLiraz, O., Boehm-Cagan, A., & Michaelson, D. M. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-16 · Cited by 118
“In view of the documented presynaptic and mitochondria-related effects of apoE4 and the cross talk between apoE4 and tau [32,33,49,50], the study focuses on these parameters and on assessing the extent to which these effects are associated with cognitive impairments and the age at which they evolve.”
BackgroundMethodInfluentialSelf-citationABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies
Boehm-Cagan, A., Bar, R., Liraz, O., Bielicki, J. K., Johansson, J. O., & Michaelson, D. M. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-160467 · Cited by 116
“1; Media Cybernetics), as described previously [28].”
InfluentialSelf-citationFuentealba, R. A., Liu, Q., Zhang, J., Kanekiyo, T., Hu, X., Lee, J.-M., LaDu, M. J., & Bu, G. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011884 · Cited by 116
“It has been demonstrated that localization of Ab42 into lysosomes is toxic to neurons, in particular in the presence of apoE4 [20,21,22].”
BackgroundInterplay Between Mitochondrial Oxidative Disorders and Proteostasis in Alzheimer’s Disease
Llanos-González, E., Henares-Chavarino, Á. A., Pedrero-Prieto, C. M., García‐Carpintero, S., Frontiñán-Rubio, J., Sancho-Bielsa, F. J., Alcain, F. J., Peinado, J. R., Rabanal‐Ruiz, Y., & Durán‐Prado, M. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01444 · Cited by 99
“Apolipoprotein E4 (apoE4) overexpression, the main genetic risk factor for late-onset AD, could cause a hyper-generation of Aβ42 in lysosomes, leading to neuronal death in the hippocampus (Ji et al., 2006; Belinson et al., 2008).”
BackgroundKuszczyk, M. A., Sanchez, S., Pankiewicz, J., Kim, J., Duszczyk, M., Guridi, M., Asuni, A. A., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.01.034 · Cited by 89
“1764 isoform,(37,38) and intraneuronally in mice expressing human ApoE4 isoform after inhibition of Ab-degrading enzyme neprilysin.(39) Because various ApoE receptors play an important role in Ab metabolism, the effect of their overexpression on Ab pathology has been studied with various model systems.”
BackgroundOverlapped Metabolic and Therapeutic Links between Alzheimer and Diabetes
Ahmad, W. (2012) · Molecular Neurobiology · doi:10.1007/s12035-012-8352-z · Cited by 80
“High levels of ApoE4 were associated with induced Aβ generation [206].”
BackgroundSex Differences in Autophagy Contribute to Female Vulnerability in Alzheimer's Disease
Congdon, E. E. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00372 · Cited by 80
“In addition to these effects, expression of the APOE-ε4 allele in cell and animal models promotes disruption of lysosomal membranes (Ji et al., 2006; Persson et al., 2017), along with increased lysosomal activation and accumulation of Aβ and APOE (Belinson et al., 2008).”
BackgroundInfluentialThe Role of BDNF on Aging-Modulation Markers
Molinari, C. G., Morsanuto, V., Ruga, S., Notte, F., Farghali, M., Galla, R., & Uberti, F. (2020) · Brain Sciences · doi:10.3390/brainsci10050285 · Cited by 82
Amyloid-β42 alters apolipoprotein E solubility in brains of mice with five familial AD mutations
Youmans, K. L., Leung, S., Zhang, J., Maus, E., Baysac, K., Bu, G., Vassar, R., Yu, C., & LaDu, M. J. (2011) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2010.12.025 · Cited by 62
“accumulation of intraneuronal Aβ and deposition of extracellular amyloid (Belinson et al., 2008; Cataldo et al., 2004; Oakley et al., 2006; Oddo et al., 2003; Schmitz et al., 2004), these methods are not well-suited for identifying the solubility of the peptide.”
MethodApoE ε4 is associated with eIF2α phosphorylation and impaired learning in young mice
Segev, Y., Michaelson, D. M., & Rosenblum, K. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.06.020 · Cited by 72
“In addition, ApoE4 may induce memory deficit (Belinson et al., 2008; Bour et al., 2008; Grootendorst et al., 2005; Hartman et al., 2001), however, the underlying mechanisms connecting ApoE4 to AD are poorly understood.”
BackgroundSelf-citationOmtri, R. S., Davidson, M. W., Arumugam, B., Poduslo, J. F., & Kandimalla, K. K. (2012) · Molecular Pharmaceutics · doi:10.1021/mp200530q · Cited by 69
Kariv-Inbal, Z., Yacobson, S., Berkecz, R., Péter, M., Janáky, T., Lütjohann, D., Broersen, L. M., Hartmann, T., & Michaelson, D. M. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111265 · Cited by 70
“The apoE genotypes were confirmed by PCR analysis [19].”
InfluentialSelf-citationIntensive LDL-cholesterol lowering therapy and neurocognitive function
Banach, M., Rizzo, M., Nikolić, D., Howard, G., Howard, V. J., & Mikhailidis (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.11.001 · Cited by 68
Memory Deficits in APP23/ Abca1 +/− Mice Correlate with the Level of A β Oligomers
Lefterov, I. M., Fitz, N. F., Cronican, A. A., Lefterov, P., Staufenbiel, M., & Koldamova, R. P. (2009) · ASN NEURO · doi:10.1042/an20090015 · Cited by 63
“These characteristic intracellular Ab42 aggregates, which were A11-positive and likely to be Ab oligomeric structures, also corresponded to the memory deficits in those mice (Belinson et al., 2008).”
BackgroundApolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury
Crawford, F., Wood, M., Ferguson, S., Mathura, V., Gupta, P., Humphrey, J., Mouzon, B., Laporte, V., Margenthaler, E., O'Steen, B., et al. (2009) · Neuroscience · doi:10.1016/j.neuroscience.2009.01.033 · Cited by 59
Pharmacological modulation of autophagy for Alzheimer's disease therapy: Opportunities and obstacles
Deng, Z., Dong, Y., Zhou, X., Lu, J.-H., & Yue, Z. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.12.009 · Cited by 58
The Implications of Autophagy in Alzheimer’s Disease
Hamano, T., Hayashi, K., Shirafuji, N., & Nakamoto, Y. (2018) · Current Alzheimer Research · doi:10.2174/1567205015666181004143432 · Cited by 57
The Effects of APOE4 on Mitochondrial Dynamics and Proteins in vivo
Simonovitch, S., Schmukler, E., Masliah, E., Pinkas-Kramarski, R., & Michaelson, D. M. (2019) · Journal of Alzheimer's Disease · doi:10.3233/jad-190074 · Cited by 59
“COX1 and Tom40 Immunohistochemistry were performed as previously described [43].”
Self-citationIntroducing 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
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“Mice were ICV implanted with Alzet mini-osmotic pumps (model 2004; Palo Alto, CA) to the right hemisphere, as previously described [25], pumping its content in a rate of 0.”
Targeting ApoE4/ApoE receptor LRP1 in Alzheimer's disease
Martiskainen, H., Haapasalo, A., Kurkinen, K. M. A., Pihlajamäki, J., Soininen, H. S., & Hiltunen, M. O. (2013) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2013.789862 · Cited by 49
“aggregation of Ab42 [42] and that accumulation of Ab42 into neuronal lysosomes is toxic to the cells, especially when Ab is associated with ApoE4 [43-45].”
BackgroundMolecular Mechanism of Autophagy: Its Role in the Therapy of Alzheimer’s Disease
Zhao, Y., Zhang, Y., Zhang, J., Zhang, X., & Yang, G. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200114163636 · Cited by 40
“Studies from Neuro2a cells and transgenic mice have shown that ApoE4 potentiates lysosomal leakage and apoptosis induced by Aβ peptides [41, 42].”
BackgroundComprehensive Overview of Alzheimer’s Disease: Etiological Insights and Degradation Strategies
Singh, M. K., Shin, Y., Ju, S., Han, S., Kim, S. S., & Kang, I. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25136901 · Cited by 43
“In ApoE4 transgenic mice, elevated levels of A β 42 in the lysosomes lead to neuronal cell death in the hippocampus [100].”
BackgroundBelinson, H., & Michaelson, D. M. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0218-9 · Cited by 38
“Immunofluorescence staining of Ab and NeuN was performed with donkey anti-rabbit 488 and Avidin 633, respectively and visualized with LSM510 confocal microscope (Zeiss), as previously described (Belinson et al. 2008).”
BackgroundMethodResultInfluentialSelf-citationApoE isoform-specific regulation of regeneration in the peripheral nervous system
Comley, L. H., Fuller, H. R., Wishart, T. M., Mutsaers, C. A., Thomson, D., Wright, A. K., Ribchester, R. R., Morris, G. E., Parson, S. H., Horsburgh, K. J., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr147 · Cited by 37
The Interplay Between Apolipoprotein E4 and the Autophagic–Endocytic–Lysosomal Axis
Schmukler, E., Michaelson, D. M., & Pinkas-Kramarski, R. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0892-4 · Cited by 35
Self-citationHuman APOE genotype affects intraneuronal A 1-42 accumulation in a lentiviral gene transfer model
Zhao, W., Dumanis, S. B., Tamboli, I. Y., Rodriguez, G. A., Jo LaDu, M., Moussa, C. E. H., & William Rebeck, G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddt525 · Cited by 32
“Inhibition of Ab-degrading enzyme neprilysin in APOE3 and APOE4 mice led to an apoE4 isoform-specific accumulation of intraneuronal Ab, accompanied by intracellular apoE and lysosomal activation (47).”
BackgroundGunaratne, G. S., Johns, M. E., Hintz, H. M., Walseth, T. F., & Marchant, J. S. (2018) · Cell Calcium · doi:10.1016/j.ceca.2018.08.002 · Cited by 30
“These data evidence lysosomal alterations which, as seen in other neurodegenerative models [18] , dysregulate NAADP action.”
Differential effects of apoE4 and activation of ABCA1 on brain and plasma lipoproteins
Boehm-Cagan, A., Bar, R., Harats, D., Shaish, A., Levkovitz, H., Bielicki, J. K., Johansson, J. O., & Michaelson, D. M. (2016) · PLOS ONE · doi:10.1371/journal.pone.0166195 · Cited by 29
Self-citationMouse Models of Alzheimer’s Dementia: Current Concepts and New Trends
Torres‐Alemán, I. (2008) · Endocrinology · doi:10.1210/en.2008-0905 · Cited by 28
“The pathogenic contribution of the 4 isoform of apolipoprotein E and its relation to cholesterol metabolism in late-onset forms is also actively studied (31), together with Torres-Aleman • Minireview Endocrinology, December 2008, 149(12):5952–5957 5953”
BackgroundApoE4 Induces Synaptic and ERG Impairments in the Retina of Young Targeted Replacement ApoE4 Mice
Antes, R., Ezra-Elia, R., Weinberger, D., Solomon, A., Ofri, R., & Michaelson, D. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064949 · Cited by 29
“In the brain, apoE4 interacts synergistically with Ab [34,43,51,52] and it remains to be determined whether similar mechanisms also mediate the effects of apoE4 in the retina.”
BackgroundSelf-citationGarai, K., Baban, B. A., & Frieden, C. (2011) · Biochemistry · doi:10.1021/bi2006702 · Cited by 27
O’Keefe, L. V., & Denton, D. (2018) · BioMed Research International · doi:10.1155/2018/5195416 · Cited by 25
“Transgenic mice that overexpress ApoE4 accumulate Aβ42 in lysosomes and there is death of neurons in the hippocampus [103].”
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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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