Cholinergic systems and long-term potentiation in memory-impaired apolipoprotein E-deficient mice
Abstract
Impairments in cholinergic neurotransmitter systems of the basal forebrain are a hallmark of Alzheimer's disease pathophysiology. The presence of the epsilon4 allele of apolipoprotein E was recently implicated as a major risk factor in both familial and sporadic Alzheimer's disease. The present study examined the integrity of cholinergic and non-cholinergic systems in apolipoprotein E-deficient, memory-impaired mice. Choline acetyltransferase activity, hippocampal acetylcholine release, nicotinic and muscarinic (M1 and M2) receptor binding sites and acetylcholinesterase cell or terminal density showed no signs of alteration in either three-month or 9.5-month-old apolipoprotein E-deficient mice compared to controls. In contrast, long-term potentiation was found to be markedly reduced in these mice, but increases in the strength of stimulation induced the same level of long-term potentiation as that observed in controls. These alterations did not appear to be the consequence of modifications in the binding properties of glutamatergic receptors (N-methyl-D-aspartate and [RS]-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) but from defective regulation of the (RS)-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid receptor by phospholipase A2 activity. These results support the notion that apolipoprotein E plays a fundamental role in neuronal plasticity, which could in turn affect cognitive performance through imbalances in extra- and intracellular lipid homeostasis.
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Apoe-deficient mice exhibit LTP deficits.
“Given the LTP deficits observed in Apoe-deficient mice [68]”
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Self-citationApolipoprotein E and Alzheimer's disease: the protective effects of ApoE2 and E3
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Kheirandish, L., Row, B. W., Li, R. C., Brittian, K. R., & Gozal, D. (2005) · SLEEP · doi:10.1093/sleep/28.11.1412 · Cited by 89 · see citing works
G protein-coupled receptor systems and their lipid environment in health disorders during aging
Alemany, R., Perona, J. S., Sánchez-Domínguez, J. M., Montero, E., Cañizares, J., Bressani, R., Escribá, P. V., & Ruíz-Gutiérrez, V. (2006) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2006.09.024 · Cited by 86 · see citing works
“On the other hand, some membrane alterations could in part explain the cognitive deficits reported in mice with neurodegenerative disorders [130,131], as well as the impaired neurotransmitter-associated signaling observed in AD and aging [132,133].”
BackgroundOlfactory function in apoE knockout mice
Nathan, B. P., Yost, J., Litherland, M. T., Struble, R. G., & Switzer, P. V. (2003) · Behavioural Brain Research · doi:10.1016/s0166-4328(03)00219-5 · Cited by 83 · see citing works
“Several previous studies have found cognitive deficit in apoE KO mice; however, these findings are controversial [1,17,18,21,23,25,37,42,44,49,55] .”
BackgroundResting-State Functional Connectivity Changes in Aging apoE4 and apoE-KO Mice
Zerbi, V., Wiesmann, M., Emmerzaal, T. L., Jansen, D., Beek, M. V., Mutsaers, M. P. C., Beckmann, C. F., Heerschap, A., & Kiliaan, A. J. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0684-14.2014 · Cited by 80 · see citing works
“, 2006) and cognitive performance (Gordon et al., 1995; Masliah et al., 1995; Oitzl et al., 1997; Krzywkowski et al., 1999).”
BackgroundMulder, M., Blokland, A., van den Berg, D.-J., Schulten, H., Bakker, A. H. F., Terwel, D., Honig, W., de Kloet, E. R., Havekes, L. M., Steinbusch, H. W. M., et al. (2001) · Laboratory Investigation · doi:10.1038/labinvest.3780307 · Cited by 74 · see citing works
“Mice deficient in apoE display disturbances in learning and memory function as well as in long-term potentiation (Krugers et al, 1997; Krzywkowski et al, 1999; Oitzl et al, 1997; Veinbergs and Masliah, 1999).”
BackgroundResultList of transgenic and knockout mice: behavioral profiles
Bolivar, V. J., Cook, M. N., & Flaherty, L. A. (2000) · Mammalian Genome · doi:10.1007/s003350010051 · Cited by 71 · see citing works
“…et al. 1998 N N L Okuyama et al. 1999 H H N Ichiki et al. 1995; Okuyama et al. 1999 Hein et al. 1995 Oitzl et al. 1997b Gordon et al. 1995, 1996b; Krzywkowski et al. 1999; Masliah et al. 1997, 1999 N* Anderson and Higgins 1997; Zhou et al. 1998 *females—12 mo.;+males L H L Muller et al. 1994;…”
Grootendorst, J., de Kloet, E. R., Dalm, S., & Oitzl, M. S. (2001) · Neuroscience · doi:10.1016/s0306-4522(01)00412-2 · Cited by 64 · see citing works
Champagne, D. L., Dupuy, J.-B., Rochford, J. M., & Poirier, J. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00313-5 · Cited by 61 · see citing works
Self-citationGrootendorst, J., de Kloet, E. R., Vossen, C., Dalm, S., & Oitzl, M. S. (2001) · Behavioural Brain Research · doi:10.1016/s0166-4328(01)00294-7 · Cited by 62 · see citing works
Hayashi, H., Campenot, R. B., Vance, D. E., & Vance, J. E. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.039560 · Cited by 58 · see citing works
Genetic Factors in Outcome After Traumatic Brain Injury
Diaz-Arrastia, R. R., & Baxter, V. K. (2006) · Journal of Head Trauma Rehabilitation · doi:10.1097/00001199-200607000-00007 · Cited by 57 · see citing works
Härtig, W., Bauer, A., Brauer, K., Grosche, J., Hortobágyi, T., Penke, B., Schliebs, R., & Harkany, T. (2002) · Reviews in the Neurosciences · doi:10.1515/revneuro.2002.13.2.95 · Cited by 49 · see citing works
Function and Comorbidities of Apolipoprotein E in Alzheimer′s Disease
Leduc, V., Domenger, D., Beaumont, L. D., Lalonde, D., Jasmin, S. B., & Poirier, J. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/974361 · Cited by 45 · see citing works
“[172] P.”
Self-citationVercauteren, F., Clerens, S., Roy, L., Hamel, N., Arckens, L., Vandesande, F., Alhonen, L. I., Jänne, J., Szyf, M., & Cuello, A. C. (2004) · Molecular Brain Research · doi:10.1016/j.molbrainres.2004.10.012 · Cited by 40 · see citing works
Age-related influence of the HDL receptor SR-BI on synaptic plasticity and cognition
Chang, E. H., Rigotti, A., & Huerta, P. T. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.07.006 · Cited by 35 · see citing works
“These mice also exhibit cognitive deficits, being impaired in the Morris water maze task at both 2 and 6 months of age [38].”
BackgroundValastro, B. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00177-9 · Cited by 36 · see citing works
Acı́n, S., Navarro, M. Á., Perona, J. S., Surra, J. C., Guillén, N., Arnal, C., Sarría, A. J., Arbonés-Mainar, J. M., Carnicer, R., Ruíz-Gutiérrez, V., et al. (2007) · British Journal Of Nutrition · doi:10.1017/s0007114507657912 · Cited by 34 · see citing works
“ApoE-deficient mice develop spontaneous atherosclerosis (Osada et al. 2000) and cognitive deficits resembling those of Alzheimer’s disease and ageing, and therefore provide a model for all these problems (Masliah et al. 1995; Oitzl et al. 1997; Krzywkowski et al. 1999).”
BackgroundJansen, D., Zerbi, V., Janssen, C. I. F., van Rooij, D., Zinnhardt, B., Dederen, P. J. W. C., Wright, A. J., Broersen, L. M., Lütjohann, D., Heerschap, A., et al. (2013) · Brain Structure and Function · doi:10.1007/s00429-013-0606-7 · Cited by 32 · see citing works
“Previous studies have shown that under basal naive conditions, apoE ko mice are severely impaired in water maze performance (Gordon et al. 1995; Krzywkowski et al. 1999; Oitzl et al. 1997; Masliah et al. 1995).”
Grootendorst, J., Kempes, M. M., Lucassen, P. J., Dalm, S., de Kloet, E. R., & Oitzl, M. S. (2002) · Brain Research · doi:10.1016/s0006-8993(02)03399-1 · Cited by 30 · see citing works
Kitamura, H. W., Hamanaka, H., Watanabe, M., Wada, K., Yamazaki, C., Fujita, S. C., Manabe, T., & Nukina, N. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2004.07.084 · Cited by 35 · see citing works
Acetylcholine receptor and behavioral deficits in mice lacking apolipoprotein E
Siegel, J. A., Benice, T. S., van Meer, P., Park, B. S., & Raber, J. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.12.006 · Cited by 28 · see citing works
“This is in contrast to Krzywkowski et al., who reported no genotype differences in these receptors in Apoe+/+ and Apoe−/− mice using autoradiography (Krzywkowski et al., 1999).”
BackgroundMethodResultInfluentialThe cognitive impact of nutritional homocysteinemia in Apolipoprotein-E deficient mice
Troen, A. M., Shukitt‐Hale, B., Chao, W., Albuquerque, B., Smith, D. E., Selhub, J., & Rosenberg, I. H. (2006) · Journal of Alzheimer s Disease · doi:10.3233/jad-2006-9403 · Cited by 28 · see citing works
“Several studies have observed cholinergic deficits and impaired MWM performance in ApoE-deficient mice aged 6–12 months [16,22,23,48] although the extent of these deficits is uncertain [2,3,36,50,74].”
Yun, S. H., Park, K. A., Sullivan, P. M., Pasternak, J. F., LaDu, M. J., & Trommer, B. L. (2005) · Journal of Neuroscience Research · doi:10.1002/jnr.20684 · Cited by 27 · see citing works
“For example, several investigators have shown that apoE-deficient (apoE-KO) mice show a significant reduction of LTP compared with wild-type (wt) mice (Krugers et al., 1997; Veinbergs et al., 1998; Krzywkowski et al., 1999; Valastro et al., 2001).”
BackgroundBronfman, F. C., Tesseur, I. C., Hofker, M. H., Havekens, L. M., & LEUVEN, F. V. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00016-6 · Cited by 26 · see citing works
Alemany, R., Navarro, M. Á., Vögler, O., Perona, J. S., Osada, J., & Ruíz-Gutiérrez, V. (2009) · Lipids · doi:10.1007/s11745-009-3370-y · Cited by 25 · see citing works
“This would counteract the impaired neurotransmittermediated signal transduction that has been reported in apoE KO mice [8].”
BackgroundCognitive Impairment in Neurological Diseases: Lessons from Apolipoprotein E
Shi, J., Han, P., & Kuniyoshi, S. M. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130623 · Cited by 22 · see citing works
“LTP has been reported to be reduced in mice with ApoE4, and this correlates with recent reports indicating that ApoE4 limits the influx of calcium induced by reelin on glutamate receptors [22, 40].”
ResultAge-related Alterations of Apolipoprotein E and Interleukin-1β in the Aging Brain
Gee, J. R., Ding, Q., & Keller, J. N. (2006) · Biogerontology · doi:10.1007/s10522-005-6039-9 · Cited by 21 · see citing works
“Indeed ApoE knockout mice possess deficits in LTP and learning and memory compared to wildtype controls, observations which are reversed upon brain infusion of ApoE (Masliah et al. 1997; Krzywkowski et al. 1999).”
BackgroundGuerini, F. R., Farina, E., Costa, A. S., Baglio, F., Saibene, F. L., Margaritella, N., Calabrese, E., Zanzottera, M., Bolognesi, E., Nemni, R., et al. (2016) · Neurorehabilitation and neural repair · doi:10.1177/1545968316642523 · Cited by 20 · see citing works
Apolipoprotein E deficiency effects on learning in mice are dependent upon the background strain
Lominska, C. E., Levin-Allerhand, J. A., Wang, J., Sikes, J. L., Kao, C., & Smith, J. D. (2001) · Behavioural Brain Research · doi:10.1016/s0166-4328(00)00365-x · Cited by 18 · see citing works
Grootendorst, J., Oitzl, M. S., Dalm, S., Enthoven, L., Schachner, M., de Kloet, E. R., & Sandi, C. (2001) · European Journal of Neuroscience · doi:10.1046/j.0953-816x.2001.01766.x · Cited by 18 · see citing works
“…mice has been reported by several groups (Gordon et al., 1995; Masliah et al., 1995; Oitzl et al., 1997; Raber et al., 1998; Zhou et al., 1998; Krzywkowski et al., 1999), although some groups could not detect differences in hippocampus-dependent behavioural tasks (Anderson et al., 1998;…”
BackgroundEkuni, D., Endo, Y., Tomofuji, T., Azuma, T., Irie, K., Kasuyama, K., & Morita, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074966 · Cited by 16 · see citing works
“Some studies show that apoE-deficient mice display a learning deficit in complex tasks involving hippocampal functions [41-46].”
BackgroundAlteration of nitric oxide synthase activity in young and aged apolipoprotein E-deficient mice
Law, A. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00068-4 · Cited by 14 · see citing works
Yesiltepe, M., Yin, T., Tambini, M., Bao, H., Pan, M., d’Abramo, C., Giliberto, L., Han, X., & D’Adamio, L. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01832-2 · Cited by 10 · see citing works
“Given the LTP deficits observed in Apoe -deficient mice [68], we measured I/O and LTP responses to assess the effects of APOE variants on synaptic plasticity in the Schafer collateral-CA1 circuit using hippocampal slices from humanized APOE variant-carrying rats.”
MethodMemory Function in a Mouse Genetic Model of Alzheimer's Disease
Avdesh, A., Wong, P., Martins, R. N., & Martin-Iverson, M. T. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101944 · Cited by 10 · see citing works
Low-dose nicotine facilitates spatial memory in ApoE-knockout mice in the radial arm maze
Sultana, R., Ameno, K., Jamal, M., Miki, T., Tanaka, N., Ono, J., Kinoshita, H., & Nakamura, Y. (2012) · Neurological Sciences · doi:10.1007/s10072-012-1149-z · Cited by 9 · see citing works
Lestaevel, P., Airault, F., Racine, R., Bensoussan, H., Dhieux, B., Delissen, O., Manens, L., Aigueperse, J., Voisin, P., & Souidi, M. (2013) · Journal of Molecular Neuroscience · doi:10.1007/s12031-013-0038-0 · Cited by 9 · see citing works
“Next, the second aim of this study was to examine if a stressor, such as uranium, a heavy metal naturally found in the environment, could induce a worsening physiopathology of ApoE−/−mice at the level of behaviour and cholesterol and acetylcholine metabolisms in normal and enriched housing conditions.”
Hernandez Torres, L. D., Rezende, F., Peschke, E., Will, O., Hövener, J.-B., Spiecker, F., Özorhan, Ü., Lampe, J., Stölting, I., Aherrahrou, Z., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1338458 · Cited by 8 · see citing works
Pharmacogenomics and the Treatment of Sporadic Alzheimers Disease:A Decade of Progress
Poirier, J., & Gauthier, S. G. (2008) · Current pharmacogenomics and personalized medicine (Online)/Current pharmacogenomics and personalized medicine · doi:10.2174/187569208784017494 · Cited by 7 · see citing works
Self-citationHayashi, T., Kamada, H., Jin, G., Deguchi, K., Nagotani, S., Sehara, Y., Zhang, H., Nagano, I., Shoji, M., & Abe, K. (2006) · Neurological Research · doi:10.1179/016164105x40002 · Cited by 7 · see citing works
Everett, A. W., & Ernst, E. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2003.10.006 · Cited by 5 · see citing works
Huang, Y., Chan, H., Khoo, J.-Y., Chan, M.-L., Bender, D. A., Ponnusamy, V. K., Belaidi, A. A., & Ke, L. (2025) · Neurochemistry International · doi:10.1016/j.neuint.2025.106104 · Cited by 4 · see citing works
Molecular Aspects of Memory Dysfunction in Alzheimer’s Disease
Chin, J., Roberson, E. D., & Mucke, L. (2008) · Elsevier eBooks · doi:10.1016/b978-012370509-9.00015-2 · Cited by 4 · see citing works
Aging-Related Memory Disorders—Alzheimer’s Disease
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Aging-Related Memory Disorders
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Self-citationGenetic Risk Factors: Their Function and Comorbidities in Alzheimer′s Disease
Hiltunen, M. O., Bertram, L., & Saunders, A. J. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/925362 · Cited by 1 · see citing works
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Self-citationKoutseff, A. (2011) · OpenGrey (Institut de l'Information Scientifique et Technique)
Jamal, M., Ameno, K., Tanaka, N., & Kinoshita, H. (2014) · Neurochemical Journal · doi:10.1134/s1819712414010073
Ruby, M., Ameno, K., Jamal, M., Miki, T., Tanaka, N., Kinoshita, H., & Nakamura, Y. (2013) · Journal of Neurology Research · doi:10.4021/jnr.v3i3-4.231
“To support this hypothesis, a number of studies have been carried out in ApoE-knockout (ApoE-KO) mice, and their results have revealed a greater attenuation of long-term potentiation (LTP) compared with WT mice [12, 13].”
ResultResting-StateFunctionalConnectivityChangesinAging apoE4andapoE-KOMice
Mutsaers, C., & Beckmann, C. (2014)
Jansen, D., Zerbi, V., Janssen, C. I. F., van Rooij, D., Dederen, P. J. W. C., Heerschap, A., & Broersen, L. M. (2013)
Ruby (2013) · Journal of Neurology Research · doi:10.4021/jnr217e
Behavioral Aspects of Apolipoprotein E Knockout Mice
Litherland, M. T. (2003)
Olfactory Behavior in ApoE Knockout Mice
Yost, J. (2001) · Journal of Collective Bargaining in the Academy
Effects of Apolipoprotein E on Neurite Outgrowth from Adult Mice Cortical Neurons
Jiang, Y. (2000) · Journal of Collective Bargaining in the Academy
- Authors
- Krzywkowski, P., Ghribi, O., Gagné, J., Chabot, C., Kar, S., Rochford, J., Massicotte, G., & Poirier, J.
- Affiliations
- Douglas Mental Health University Institute (CA)
- Université du Québec à Trois-Rivières (CA)
- Corresponding author
- Poirier, J.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 1999-06
- Volume
- 92
- Issue
- 4
- Pages
- 1273-1286
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2043012963
- Cited by
- 74
- References
- 81
- Citations by year
- 2025: 1 · 2024: 2 · 2017: 1 · 2016: 1 · 2014: 5 · 2013: 7 · 2012: 1
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- apolipoprotein E deficiency, APOE ε4, Alzheimer's disease, cholinergic system, long-term potentiation, memory impairment, hippocampus, nicotinic acetylcholine receptors, muscarinic receptors, acetylcholinesterase, choline acetyltransferase, glutamate receptors, NMDA receptor, AMPA receptors, phospholipase A2, neuroplasticity, lipid homeostasis, basal forebrain
- MeSH terms
- Acetylcholine, Acetylcholinesterase, Animals, Apolipoproteins E, Autoradiography, Brain, Choline O-Acetyltransferase, Histocytochemistry, Memory Disorders, Mice, Inbred C57BL, Parasympathetic Nervous System, Phospholipases A, Receptors, Muscarinic, Receptors, Nicotinic, Long-Term Potentiation, Mice, Knockout, Glutamic Acid, Maze Learning, Mice, Phospholipases A2
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