Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2
Open accessAbstract
Inheritance of the APOE4 allele is a well established genetic risk factor linked to the development of late onset Alzheimer's disease. As the major lipid transport protein in the central nervous system, apolipoprotein (apo) E plays an important role in the assembly and maintenance of synaptic connections. Our previous work showed that 7 month old human apoE4 targeted replacement (TR) mice displayed significant synaptic deficits in the principal neurons of the lateral amygdala, a region that is critical for memory formation and also one of the primary regions affected in Alzheimer's disease, compared to apoE3 TR mice. In the current study, we determined how age and varying APOE genotype affect synaptic integrity of amygdala neurons by comparing electrophysiological and morphometric properties in C57BL6, apoE knockout, and human apoE3, E4 and E2/4 TR mice at 1 month and 7 months. The apoE4 TR mice exhibited the lowest level of excitatory synaptic activity and dendritic arbor compared to other cohorts at both ages, and became progressively worse by 7 months. In contrast, the apoE3 TR mice exhibited the highest synaptic activity and dendritic arbor of all cohorts at both ages. C57BL6 mice displayed virtually identical synaptic activity to apoE3 TR mice at 1 month; however this activity decreased by 7 months. ApoE knockout mice exhibited a similar synaptic activity profile with apoE4 TR mice at 7 months. Consistent with previous reports that APOE2 confers protection, the apoE4-dependent deficits in excitatory activity were significantly attenuated in apoE2/4 TR mice at both ages. These findings demonstrate that expression of human apoE4 contributes to functional deficits in the amygdala very early in development and may be responsible for altering neuronal circuitry that eventually leads to cognitive and affective disorders later in life.
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.
Integrity signals
Registry
Cites
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.
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?
Forced expression of ApoE2 attenuated the progressive loss of synaptic integrity induced by ApoE4.
“Forced expression of ApoE2 attenuated the progressive loss of synaptic integrity induced by ApoE4 (Klein et al., 2010).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Klein et al., 2010
The Discussion reports that co-expression of apoE2 with apoE4 attenuated loss of synaptic activity in the lateral amygdala, but did not alter dendritic length. The Preparation of animals section describes apoE2/4 heterozygous targeted-replacement mice, not forced expression of apoE2. Thus the attenuation is supported for synaptic activity, but the stated intervention and broader implication for synaptic integrity are not fully supported. (LLM, conf=0.88)
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
THE AMYGDALA MODULATES THE CONSOLIDATION OF MEMORIES OF EMOTIONALLY AROUSING EXPERIENCES
McGaugh, J. L. (2004) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.27.070203.144157 · Cited by 2,296 · see citing works
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920 · see citing works
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
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 · see citing works
Self-citationImpact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels
Riddell, D. R., Zhou, H., Atchison, K., Warwick, H. K., Atkinson, P. J., Jefferson, J., Xu, L., Aschmies, S., Kirksey, Y., Hu, Y., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1972-08.2008 · Cited by 342 · see citing works
Human<i>APOE</i>Isoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice
Bales, K. R., Liu, F., Wu, S., Lin, S., Koger, D., DeLong, C., Hansen, J. C., Sullivan, P. M., & Paul, S. M. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.0887-09.2009 · Cited by 274 · see citing works
Self-citationSullivan, P. M., Mezdour, H., Quarfordt, S. H., & Maeda, N. (1998) · Journal of Clinical Investigation · doi:10.1172/jci2673 · Cited by 254 · cited 2× · see citing works
“hyperlipidemia (Sullivan et al., 1998), a chronic pro-inflammatory state that can confound interpretation of CNS phenotypes.”
Self-citationApolipoprotein E and cognitive performance
Raber, J., Wong, D., Yu, G.-Q., Buttini, M., Mahley, R. W., Pitas, R. E., & Mucke, L. (2000) · Nature · doi:10.1038/35006165 · Cited by 237 · see citing works
ApoE4 Decreases Spine Density and Dendritic Complexity in Cortical Neurons<i>In Vivo</i>
Dumanis, S. B., Tesoriero, J. A., Babus, L. W., Nguyen, M. T., Trotter, J. H., Ladu, M. J., Weeber, E. J., Turner, R. S., Xu, B., Rebeck, G. W., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.4026-09.2009 · Cited by 220 · see citing works
Buttini, M., Yu, G.-Q., Shockley, K., Huang, Y., Jones, B., Masliah, E., Mallory, M., Yeo, T., Longo, F. M., & Mucke, L. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-24-10539.2002 · Cited by 183 · cited 1× · see citing works
“plaques and tangles) (Buttini et al., 2002) (Mucke et al.”
Fagan, A. M., Murphy, B. A., Patel, S. N., Kilbridge, J. F., Mobley, W. C., Bu, G., & Holtzman, D. M. (1998) · Experimental Neurology · doi:10.1006/exnr.1998.6818 · Cited by 116 · see citing works
APOE related alterations in cerebral activation even at college age
Scarmeas, N. (2005) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2004.053645 · Cited by 97 · see citing works
ApoE isoform-dependent changes in hippocampal synaptic function
Korwek, K. M., Trotter, J. H., LaDu, M. J., Sullivan, P. M., & Weeber, E. J. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-21 · Cited by 89 · see citing works
Self-citationApoE 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 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 46
- Acevedo SF Piper BJ Craytor MJ Benice TS Raber J Apolipoprotein E4 and sex affect neurobehavioral performance in primary school children Pediatr Res 2010 67 293 299 19952867 PMC2853744
- Akirav I Richter-Levin G Mechanisms of amygdala modulation of hippocampal plasticity Journal of Neuroscience 2002 22 9912 9921 12427848 PMC6757810
- Anderson R Barnes JC Bliss TV Cain DP Cambon K Davies HA Errington ML Fellows LA Gray RA Hoh T Stewart M Large CH Higgins GA Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse Neuroscience 1998 85 93 110 9607706
- Basso M Gelernter J Yang J MacAvoy MG Varma P Bronen RA van Dyck CH Apolipoprotein E epsilon4 is associated with atrophy of the amygdala in Alzheimer's disease Neurobiol Aging 2006 27 1416 1424 16182410
- Blain JF Sullivan PM Poirier J A deficit in astroglial organization causes the impaired reactive sprouting in human apolipoprotein E4 targeted replacement mice Neurobiol Dis 2006 21 505 514 16171999
- Blair CK Folsom AR Knopman DS Bray MS Mosley TH Boerwinkle E APOE genotype and cognitive decline in a middle-aged cohort Neurology 2005 64 268 276 15668424
- Bohnet K Pillot T Visvikis S Sabolovic N Siest G Apolipoprote in (apo) E genotype and apoE concentration determine binding of normal very low density lipoproteins to HepG2 cell surface receptors Journal of Lipid Research 1996 37 1316 1324 8808766
- Bour A Grootendorst J Vogel E Kelche C Dodart JC Bales K Moreau PH Sullivan PM Mathis C Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks Behavioural brain research 2008a 18572260
- Bour A Grootendorst J Vogel E Kelche C Dodart JC Bales K Moreau PH Sullivan PM Mathis C Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks Behav Brain Res 2008b 193 174 182 18572260
- Bourre JM Francois M Youyou A Dumont O Piciotti M Pascal G Durand G The effects of dietary alpha-linolenic acid on the composition of nerve membranes, enzymatic activity, amplitude of electrophysiological parameters, resistance to poisons and performance of learning tasks in rats J Nutr 1989 119 1880 1892 2576038
- Corder EH Saunders AM Strittmatter WJ Schmechel DE Gaskell PC Small GW Roses AD Haines JL Pericak-Vance MA Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families Science 1993 261 921 923 8346443
- Cuenod CA Denys A Michot JL Jehenson P Forette F Kaplan D Syrota A Boller F Amygdala atrophy in Alzheimer's disease. An in vivo magnetic resonance imaging study Arch Neurol 1993 50 941 945 8363448
- Faber ES Callister RJ Sah P Morphological and electrophysiological properties of principal neurons in the rat lateral amygdala in vitro Journal of neurophysiology 2001 85 714 723 11160506
- Fried I Wilson CL Morrow JW Cameron KA Behnke ED Ackerson LC Maidment NT Increased dopamine release in the human amygdala during performance of cognitive tasks Nature Neuroscience 2001 4 201 206 11175882
- Ganguli M Chandra V Kamboh MI Johnston JM Dodge HH Thelma BK Juyal RC Pandav R Belle SH DeKosky ST Apolipoprotein E polymorphism and Alzheimer disease: The Indo-US Cross-National Dementia Study Arch Neurol 2000 57 824 830 10867779
- Goritz C Mauch DH Nagler K Pfrieger FW Role of glia-derived cholesterol in synaptogenesis: new revelations in the synapse-glia affair J Physiol Paris 2002 96 3–4 257 263 12445904
- Grootendorst JBA Vogel E Kelche C Sullivan PM Dodart JC Bales K Mathis C Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior Behavioral Brain Research 2005 159 1 14 15794991
- Grootendorst J Bour A Vogel E Kelche C Sullivan PM Dodart JC Bales K Mathis C Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior Behavioural brain research 2005 159 1 14 15794991
- Hamann S Monarch ES Goldstein FC Impaired fear conditioning in Alzheimer's disease Neuropsychologia 2002 40 1187 1195 11931922
- Hering H Lin CC Sheng M Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability Journal of Neuroscience 2003 23 3262 3271 12716933 PMC6742299
- Hixson JE Vernier DT Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI Journal of Lipid Research 1990 31 545 548 2341813
- Ji Y Gong Y Gan W Beach T Holtzman DM Wisniewski T Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients Neuroscience 2003 122 305 315 14614898
- Klein RC Yakel JL Functional somato-dendritic alpha7-containing nicotinic acetylcholine receptors in the rat basolateral amygdala complex J Physiol 2006 576 865 872 16931547 PMC1890412
- Koudinov AR Koudinova NV Essential role for cholesterol in synaptic plasticity and neuronal degeneration FASEB Journal 2001 15 1858 1860 11481254
- Krugers HJ Mulder M Korf J Havekes L de Kloet ER Joels M Altered synaptic plasticity in hippocampal CA1 area of apolipoprotein E deficient mice Neuroreport 1997 8 2505 2510 9261817
- Mahley RW Apolipoprotein E: cholesterol transport protein with expanding role in cell biology Science 1988 240 622 630 3283935
- McDonald AJ Muller JF Mascagni F GABAergic innervation of alpha type II calcium/calmodulin-dependent protein kinase immunoreactive pyramidal neurons in the rat basolateral amygdala J Comp Neurol 2002 446 199 218 11932937
- Mucke L Masliah E Yu GQ Mallory M Rockenstein EM Tatsuno G Hu K Kholodenko D Johnson-Wood K McConlogue L High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation Journal of Neuroscience 2000 20 4050 4058 10818140 PMC6772621
- Murthy M Hamilton J Greiner RS Moriguchi T Salem N Jr Kim HY Differential effects of n-3 fatty acid deficiency on phospholipid molecular species composition in the rat hippocampus Journal of Lipid Research 2002 43 611 617 11907144
- Osorio C Sullivan PM He DN Mace BE Ervin JF Strittmatter WJ Alzate O Mortalin is regulated by APOE in hippocampus of AD patients and by human APOE in TR mice Neurobiol Aging 2007 28 1853 1862 17050040
- Poirier J Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease Trends in Neurosciences 1994 17 525 530 7532337
- Raber J Role of apolipoprotein E in anxiety Neural Plast 2007 2007 91236 17710250 PMC1940061
- Reiman EM Chen K Alexander GE Caselli RJ Bandy D Osborne D Saunders AM Hardy J Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia Proceedings of the National Academy of Sciences of the United States of America 2004 101 284 289 14688411 PMC314177
- Riley KP Snowdon DA Markesbery WR Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study Annals of Neurology 2002 51 567 577 12112102
- Roses AD Saunders AM Alberts MA Strittmatter WJ Schmechel D Gorder E Pericak-Vance MA Apolipoprotein E E4 allele and risk of dementia Jama 1995 273 374 375 author reply 375–376. 7823377
- Rubinsztein DC Easton DF Apolipoprotein E genetic variation and Alzheimer's disease. a meta-analysis Dementia & Geriatric Cognitive Disorders 1999 10 199 209 10325447
- Saunders AM Strittmatter WJ Schmechel D George-Hyslop PH Pericak-Vance MA Joo SH Rosi BL Gusella JF Crapper-MacLachlan DR Alberts MJ Hulette C Crain B Goldgaber D Roses AD Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease Neurology 1993 43 1467 1472 8350998
- Siegel JA Haley GE Raber J Apolipoprotein E isoform-dependent effects on anxiety and cognition in female TR mice Neurobiol Aging 2010 PMC2935518 20400205
- Snowdon DA Greiner LH Markesbery WR Linguistic ability in early life and the neuropathology of Alzheimer's disease and cerebrovascular disease. Findings from the Nun Study Annals of the New York Academy of Sciences 2000 903 34 38 10818486
- Sullivan PM Han B Liu F Mace BE Ervin JF Wu S Koger D Paul S Bales KR Reduced levels of human apoE4 protein in an animal model of cognitive impairment Neurobiol Aging 2009 19577821
- Terry RD Masliah E Salmon DP Butters N DeTeresa R Hill R Hansen LA Katzman R Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment Annals of Neurology 1991 30 572 580 1789684
- Trommer BL Shah C Yun SH Gamkrelidze G Pasternak ES Ye GL Sotak M Sullivan PM Pasternak JF LaDu MJ ApoE isoform affects LTP in human targeted replacement mice Neuroreport 2004 15 2655 2658 15570172
- Veinbergs I Mante M Jung MW Van Uden E Masliah E Synaptotagmin and synaptic transmission alterations in apolipoprotein E-deficient mice Prog Neuropsychopharmacol Biol Psychiatry 1999 23 519 531 10378234
- Wang C Wilson WA Moore SD Mace BE Maeda N Schmechel DE Sullivan PM Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology Neurobiol Dis 2005 18 390 398 15686968
- Wishart HA Saykin AJ McAllister TW Rabin LA McDonald BC Flashman LA Roth RM Mamourian AC Tsongalis GJ Rhodes CH Regional brain atrophy in cognitively intact adults with a single APOE epsilon4 allele Neurology 2006 67 1221 1224 17030756
- Yun SH Park KA Sullivan P Pasternak JF Ladu MJ Trommer BL Blockade of nicotinic acetylcholine receptors suppresses hippocampal long-term potentiation in wild-type but not ApoE4 targeted replacement mice J Neurosci Res 2005 82 771 777 16273551
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 · see citing works
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425 · see citing works
Apolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394 · see citing works
Wu, L., Zhang, X., & Zhao, L. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.2262-17.2018 · Cited by 185 · see citing works
ApoE4 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 · see citing works
The dendritic hypothesis for Alzheimer's disease pathophysiology
Cochran, J. N., Hall, A. M., & Roberson, E. D. (2014) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2013.12.004 · Cited by 114 · see citing works
Liraz, O., Boehm-Cagan, A., & Michaelson, D. M. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-16 · Cited by 118 · see citing works
Jackson, R. J., Keiser, M. S., Meltzer, J. C., Fykstra, D. P., Dierksmeier, S. E., Hajizadeh, S., Kreuzer, J., Morris, R., Melloni, A., Nakajima, T., et al. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.03.024 · Cited by 86 · see citing works
Introducing Human <i>APOE</i> into A<i>β</i> 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 · see citing works
Preman, P., Moechars, D., Fertan, E., Wolfs, L., Serneels, L., Shah, D., Lamote, J., Poovathingal, S., Snellinx, A., Mancuso, R., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00162-7 · Cited by 32 · see citing works
High-density lipoprotein-related cholesterol metabolism in Alzheimer's disease
Pedrini, S., Chatterjee, P., Hone, E., & Martins, R. N. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15170 · Cited by 22 · see citing works
- Authors
- Klein, R. C., Mace, B. E., Moore, S. D., & Sullivan, P. M.
- Affiliations
- Duke Medical Center (US)
- Duke University (US)
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 171
- Issue
- 4
- Pages
- 1265-1272
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC2991419
- OpenAlex
- W2092577192
- Cited by
- 67
- References
- 14
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 3 · 2022: 7 · 2021: 5 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 1 · 2015: 6 · 2014: 6 · 2013: 9 · 2012: 2
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG025975)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, apolipoprotein E2, targeted replacement mice, synaptic integrity, lateral amygdala, dendritic branching, ApoE-deficient mice, Alzheimer's disease risk, APOE genotype, neural circuits
- MeSH terms
- Age Factors, Amygdala, Animals, Apolipoproteins E, Genotype, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Synapses, Single-Blind Method, Patch-Clamp Techniques, Excitatory Postsynaptic Potentials, Mice, Apolipoprotein E4, Apolipoprotein E2, In Vitro Techniques
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
