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Genetic Models of Alzheimer’s Disease: The Influence of Apolipoprotein E allele Isoforms on Behaviour in Laboratory Animals

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Book cover Animal Models of Behavior Genetics

Part of the book series: Advances in Behavior Genetics ((AIBG))

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Abstract

There are several genetic factors that confer an increased risk of Alzheimer’s disease; namely mutations associated with the amyloid precursor protein, presenilin 1, presenilin 2 and the apolipoprotein E (APOE) genes. We focus here on the behavioural impact in laboratory animals of polymorphisms in the APOE gene. In humans, this gene presents in the form of three allele variants (ε2, ε3 and ε4), with the ε4 polymorphism conferring a significantly elevated risk of late-onset Alzheimer’s disease. In laboratory animals, strains of genetically altered APOE mice have been developed to investigate the association between apolipoprotein isoforms and behaviour. In this chapter, behavioural results obtained in transgenic mice on the Morris water maze, passive avoidance, novel object/place recognition, Y-maze active avoidance, elevated plus/zero maze and open field tests are summarised. Much of this literature has yielded conflicting results with respect to the impact of the ε4 allele on task performance compared with the ε3 and ε2 alleles. Furthermore, there appear to be significant age- and sex-dependent influences with respect to the impact of the ε4 isoform on memory in APOE transgenic mice. In addition, elevated anxiety/fear characteristics have been reported in APOE ε4 animals. Future studies undertaken in apoE expressing mice should increase generalisability of experimental findings by using larger sample sizes (i.e. >20 mice per group), and should also tests older animals. The latter approach is likely to address more effectively the age-by-genotype interactions which have been reported in human ε4 studies. Other potential directions for future research relate to the interactions between APOE genetic polymorphisms and other genetic (e.g. APP) and environmental (e.g. diet, activity levels) factors. It is hoped that such investigations will help to resolve some of the inconsistencies that are present in the extant literature.

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References

  • Akhtar, A. Z., Pippin, J. J., & Sandusky, C. B. (2008). Animal models in spinal cord injury: A review. Reviews in the Neurosciences, 19, 47–60. doi:10.1515/REVNEURO.2008.19.1.47.

    Article  PubMed  Google Scholar 

  • Andrews-Zwilling, Y., Bien-Ly, N., Xu, Q., Li, G., Bernardo, A., Yoon, S. Y., et al. (2010). Apolipoprotein E4 causes age- and tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. The Journal of Neuroscience, 30(41), 13707–13717. doi:10.1523/JNEUROSCI.4040-10.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Apostolova, L. G., & Thompson, P. M. (2008). Mapping progressive brain structural changes in early Alzheimer’s disease and mild cognitive impairment. Neuropsychologia, 46(6), 1597–1612. doi:10.1016/j.neuropsychologia.2007.10.026.

    Article  PubMed  Google Scholar 

  • Arnold, S. E., Hyman, B. T., Flory, J., Damasio, A. R., & Hoesen, G. W. V. (1991). The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cerebral Cortex, 1(1), 103–116. doi:10.1093/cercor/1.1.103.

    Article  CAS  PubMed  Google Scholar 

  • Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T., & Hyman, B. T. (1992). Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology, 42(3), 631–639. doi:10.1212/WNL.42.3.631.

    Article  CAS  PubMed  Google Scholar 

  • Behl, C. (1994). Hydrogen peroxide mediates amyloid β protein toxicity. Cell, 77(6), 817–827. doi:10.1016/0092-8674(94)90131-7.

    Article  CAS  PubMed  Google Scholar 

  • Behl, C., Davis, J., Cole, G. M., & Schubert, D. (1992). Vitamin E protects nerve cells from amyloid β-protein toxicity. Biochemical and Biophysical Research Communications, 186(2), 944–950. doi:10.1016/0006-291X(92)90837-B.

    Article  CAS  PubMed  Google Scholar 

  • Belinson, H., Lev, D., Masliah, E., & Michaelson, D. M. (2008). Activation of the amyloid cascade in apolipoprotein E4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. The Journal of Neuroscience, 28(18), 4690–4701. doi:10.1523/JNEUROSCI.5633-07.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bellosta, S., Nathan, B. P., Orth, M., Dong, L.-M., Mahley, R. W., & Pitas, R. E. (1995). Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth. Journal of Biological Chemistry, 270(45), 27063–27071. doi:10.1074/jbc.270.45.27063.

    Article  CAS  PubMed  Google Scholar 

  • Benice, T. S., & Raber, J. (2008). Object recognition analysis in mice using nose-point digital video tracking. Journal of Neuroscience Methods, 168(2), 422–430. doi:10.1016/j.jneumeth.2007.11.002.

    Article  CAS  PubMed  Google Scholar 

  • Berg, L., McKeel, D. W., Jr., Miller, J. P., Storandt, M., Rubin, E. H., Morris, J. C., et al. (1998). Clinicopathologic studies in cognitively healthy aging and Alzheimer disease: Relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Archives of Neurology, 55(3), 326.

    Article  CAS  PubMed  Google Scholar 

  • Bird, T. (1998). Alzheimer disease overview (Updated 2012). Seattle, WA: University of Washington. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK1161/.

  • Bird, T. (1999). Early-onset familial Alzheimer disease (Updated 2012). Seattle, WA: University of Washington. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK1236/.

    Google Scholar 

  • Bondi, M. W., Salmon, D. P., Galasko, D., Thomas, R. G., & Thal, L. J. (1999). Neuropsychological function and apolipoprotein E genotype in the preclinical detection of Alzheimer’s disease. Psychology and Aging, 14(2), 295.

    Article  CAS  PubMed  Google Scholar 

  • Bour, A., Grootendorst, J., Vogel, E., Kelche, C., Dodart, J.-C., Bales, K., et al. (2008). Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks. Behavioural Brain Research, 193(2), 174–182. doi:10.1016/j.bbr.2008.05.008.

    Article  CAS  PubMed  Google Scholar 

  • Boyles, J. K., Pitas, R. E., Wilson, E., Mahley, R. W., & Taylor, J. M. (1985). Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. Journal of Clinical Investigation, 76(4), 1501–1513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Braak, H., & Braak, E. (1991). Neuropathological stageing of Alzheimer-related changes. Acta Neuropathologica, 82(4), 239–259.

    Article  CAS  PubMed  Google Scholar 

  • Braak, E., & Braak, H. (1997). Alzheimer’s disease: Transiently developing dendritic changes in pyramidal cells of sector CA1 of the Ammon’s horn. Acta Neuropathologica, 93(4), 323–325. doi:10.1007/s004010050622.

    Article  CAS  PubMed  Google Scholar 

  • Brecht, W. J., Harris, F. M., Chang, S., Tesseur, I., Yu, G.-Q., Xu, Q., et al. (2004). Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. The Journal of Neuroscience, 24(10), 2527–2534. doi:10.1523/JNEUROSCI.4315-03.2004.

    Article  CAS  PubMed  Google Scholar 

  • Bunce, D., Fratiglioni, L., Small, B. J., Winblad, B., & Bäckman, L. (2004). APOE and cognitive decline in preclinical Alzheimer disease and non-demented aging. Neurology, 63(5), 816–821.

    Article  CAS  PubMed  Google Scholar 

  • Busciglio, J., Gabuzda, D. H., Matsudaira, P., & Yankner, B. A. (1993). Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proceedings of the National Academy of Sciences, 90(5), 2092–2096.

    Article  CAS  Google Scholar 

  • Buttini, M., Orth, M., Bellosta, S., Akeefe, H., Pitas, R. E., Wyss-Coray, T., et al. (1999). Expression of human apolipoprotein E3 or E4 in the brains of Apoe−/− mice: Isoform-specific effects on neurodegeneration. The Journal of Neuroscience, 19(12), 4867–4880.

    CAS  PubMed  Google Scholar 

  • Carrión-Baralt, J. R., Meléndez-Cabrero, J., Rodríguez-Ubiñas, H., Schmeidler, J., Beeri, M. S., Angelo, G., et al. (2009). Impact of APOE ε4 on the cognitive performance of a sample of non-demented Puerto Rican nonagenarians. Journal of Alzheimer’s Disease, 18(3), 533–540. doi:10.3233/JAD-2009-1160.

    PubMed  Google Scholar 

  • Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., et al. (2011). Human apoE isoforms differentially regulate brain amyloid-peptide clearance. Science Translational Medicine, 3(89), 89ra57. doi:10.1126/scitranslmed.3002156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaudhari, K., Wong, J. M., Vann, P. H., & Sumien, N. (2014). Exercise training and antioxidant supplementation independently improve cognitive function in adult male and female GFAP-APOE mice. Journal of Sport and Health Science, 3(3), 196–205.

    Article  Google Scholar 

  • Corder, E. H., Ghebremedhin, E., Taylor, M. G., Thal, D. R., Ohm, T. G., & Braak, H. (2004). The biphasic relationship between regional brain senile plaque and neurofibrillary tangle distributions: Modification by age, sex, and APOE polymorphism. Annals of the New York Academy of Sciences, 1019(1), 24–28. doi:10.1196/annals.1297.005.

    Article  CAS  PubMed  Google Scholar 

  • Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., et al. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science, 261(5123), 921–923. doi:10.1126/science.8346443.

    Article  CAS  PubMed  Google Scholar 

  • Cosentino, S., Scarmeas, N., Helzner, E., Glymour, M. M., Brandt, J., Albert, M., et al. (2008). APOE ε4 allele predicts faster cognitive decline in mild Alzheimer’s disease. Neurology, 70(19 Pt 2), 1842–1849. doi:10.1212/01.wnl.0000304038.37421.cc.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dantzer, R., Capuron, L., Irwin, M. R., Miller, A. H., Ollat, H., Hugh Perry, V., et al. (2008). Identification and treatment of symptoms associated with inflammation in medically ill patients. Psychoneuroendocrinology, 33(1), 18–29. doi:10.1016/j.psyneuen.2007.10.008.

    Article  PubMed  Google Scholar 

  • De Leon, M. J., Convit, A., DeSanti, S., Bobinski, M., George, A. E., Wisniewski, H. M., et al. (1997). Contribution of structural neuroimaging to the early diagnosis of Alzheimer’s disease. International Psychogeriatrics, 9(Suppl. S1), 183–190. doi:10.1017/S1041610297004900.

    Article  PubMed  Google Scholar 

  • Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B., et al. (2008). apoE isoform–specific disruption of amyloid β peptide clearance from mouse brain. The Journal of Clinical Investigation, 118(12), 4002–4013. doi:10.1172/JCI36663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eisenberg, D. T. A., Kuzawa, C. W., & Hayes, M. G. (2010). Worldwide allele frequencies of the human apolipoprotein E gene: Climate, local adaptations, and evolutionary history. American Journal of Physical Anthropology, 143(1), 100–111. doi:10.1002/ajpa.21298.

    Article  PubMed  Google Scholar 

  • Elshourbagy, N. A., Liao, W. S., Mahley, R. W., & Taylor, J. M. (1985). Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets. Proceedings of the National Academy of Sciences, 82(1), 203–207.

    Article  CAS  Google Scholar 

  • Esch, F. S., Keim, P. S., Beattie, E. C., Blacher, R. W., Culwell, A. R., Oltersdorf, T., et al. (1990). Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science, 248(4959), 1122–1124. doi:10.1126/science.2111583.

    Article  CAS  PubMed  Google Scholar 

  • Farrer, L. A., Cupples, L. A., Haines, J. L., Hyman, B., Kukull, W. A., Mayeux, R., et al. (1997). Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. JAMA, the Journal of the American Medical Association, 278(16), 1349–1356.

    Article  CAS  PubMed  Google Scholar 

  • Foster, J. K., Albrecht, M. A., Savage, G., Lautenschlager, N. T., Ellis, K. A., Maruff, P., et al. (2013). Lack of reliable evidence for a distinctive ε4–related cognitive phenotype that is independent from clinical diagnostic status: Findings from the Australian Imaging. Biomarkers and Lifestyle Study. Brain, 136(Pt 7), 2201–2216. doi:10.1093/brain/awt127.

    Article  PubMed  Google Scholar 

  • Fukumoto, H., Asami-Odaka, A., Suzuki, N., Shimada, H., Ihara, Y., & Iwatsubo, T. (1996). Amyloid beta protein deposition in normal aging has the same characteristics as that in Alzheimer’s disease. Predominance of A beta 42(43) and association of A beta 40 with cored plaques. The American Journal of Pathology, 148(1), 259–265.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gandy, S. (2005). The role of cerebral amyloid β accumulation in common forms of Alzheimer disease. Journal of Clinical Investigation, 115(5), 1121–1129. doi:10.1172/JCI200525100.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ghebremedhin, E., Schultz, C., Braak, E., & Braak, H. (1998). High frequency of apolipoprotein E ϵ4 allele in young individuals with very mild Alzheimer’s disease-related neurofibrillary changes. Experimental Neurology, 153(1), 152–155. doi:10.1006/exnr.1998.6860.

    Article  CAS  PubMed  Google Scholar 

  • Giulian, D., Haverkamp, L. J., Yu, J. H., Karshin, W., Tom, D., Li, J., et al. (1996). Specific domains of β-amyloid from Alzheimer plaque elicit neuron killing in human microglia. The Journal of Neuroscience, 16(19), 6021–6037.

    CAS  PubMed  Google Scholar 

  • Glenner, G. G., & Wong, C. W. (1984). Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical and Biophysical Research Communications, 120(3), 885–890.

    Article  CAS  PubMed  Google Scholar 

  • Gómez-Isla, T., Hollister, R., West, H., Mui, S., Growdon, J. H., Petersen, R. C., et al. (1997). Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Annals of Neurology, 41(1), 17–24. doi:10.1002/ana.410410106.

    Article  PubMed  Google Scholar 

  • Gomez-Isla, T., West, H. L., Rebeck, G. W., Harr, S. D., Growdon, J. H., Locascio, J. J., et al. (1996). Clinical and pathological correlates of apolipoprotein E ε4 in Alzheimer’s disease. Annals of Neurology, 39(1), 62–70. doi:10.1002/ana.410390110.

    Article  CAS  PubMed  Google Scholar 

  • Götz, J., Chen, F., van Dorpe, J., & Nitsch, R. M. (2001). Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science, 293(5534), 1491–1495. doi:10.1126/science.1062097.

    Article  PubMed  Google Scholar 

  • Gravina, S. A., Ho, L., Eckman, C. B., Long, K. E., Otvos, L., Younkin, L. H., et al. (1995). Amyloid β protein (Aβ) in Alzheimeri’s disease brain. Journal of Biological Chemistry, 270(13), 7013–7016. doi:10.1074/jbc.270.13.7013.

    Article  CAS  PubMed  Google Scholar 

  • Grehan, S., Tse, E., & Taylor, J. M. (2001). Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain. The Journal of Neuroscience, 21(3), 812–822.

    CAS  PubMed  Google Scholar 

  • Grootendorst, J., Bour, A., Vogel, E., Kelche, C., Sullivan, P. M., Dodart, J.-C., et al. (2005). Human apoE targeted replacement mouse lines: h-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior. Behavioural Brain Research, 159(1), 1–14. doi:10.1016/j.bbr.2004.09.019.

    Article  CAS  PubMed  Google Scholar 

  • Guo, L., LaDu, M., & Van Eldik, L. (2004). A dual role for apolipoprotein E in neuroinflammation. Journal of Molecular Neuroscience, 23(3), 205–212. doi:10.1385/JMN:23:3:205.

    Article  CAS  PubMed  Google Scholar 

  • Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfrey, C., Mellon, A., Ostaszewski, B. L., et al. (1992). Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature, 359(6393), 322–325. doi:10.1038/359322a0.

    Article  CAS  PubMed  Google Scholar 

  • Hardy, J. (1997). Amyloid, the presenilins and Alzheimer’s disease. Trends in Neurosciences, 20(4), 154–159.

    Article  CAS  PubMed  Google Scholar 

  • Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science, 297(5580), 353–356. doi:10.1126/science.1072994.

    Article  CAS  PubMed  Google Scholar 

  • Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M., et al. (2009). Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease, and shows evidence for additional susceptibility genes. Nature Genetics, 41(10), 1088–1093. doi:10.1038/ng.440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harris, F. M., Brecht, W. J., Xu, Q., Mahley, R. W., & Huang, Y. (2004). Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase modulation by Zinc. Journal of Biological Chemistry, 279(43), 44795–44801. doi:10.1074/jbc.M408127200.

    Article  CAS  PubMed  Google Scholar 

  • Harris, F. M., Brecht, W. J., Xu, Q., Tesseur, I., Kekonius, L., Wyss-Coray, T., et al. (2003). Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proceedings of the National Academy of Sciences, 100(19), 10966–10971. doi:10.1073/pnas.1434398100.

    Article  CAS  Google Scholar 

  • Harrison, N. A., Brydon, L., Walker, C., Gray, M. A., Steptoe, A., & Critchley, H. D. (2009). Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biological Psychiatry, 66(5), 407–414. doi:10.1016/j.biopsych.2009.03.015.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hartman, R. E., Wozniak, D. F., Nardi, A., Olney, J. W., Sartorius, L., & Holtzman, D. M. (2001). Behavioral phenotyping of GFAP-ApoE3 and -ApoE4 transgenic mice: ApoE4 mice show profound working memory impairments in the absence of Alzheimer’s-like neuropathology. Experimental Neurology, 170(2), 326–344. doi:10.1006/exnr.2001.7715.

    Article  CAS  PubMed  Google Scholar 

  • Huang, Y., Liu, X. Q., Wyss-Coray, T., Brecht, W. J., Sanan, D. A., & Mahley, R. W. (2001). Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proceedings of the National Academy of Sciences, 98(15), 8838–8843. doi:10.1073/pnas.151254698.

    Article  CAS  Google Scholar 

  • Iqbal, K., Liu, F., Gong, C.-X., & Grundke-Iqbal, I. (2010). Tau in Alzheimer disease and related tauopathies. Current Alzheimer Research, 7(8), 656–664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N., & Ihara, Y. (1994). Visualization of Aβ42(43) and Aβ40 in senile plaques with end-specific Aβ monoclonals: Evidence that an initially deposited species is Aβ42(43). Neuron, 13(1), 45–53. doi:10.1016/0896-6273(94)90458-8.

    Article  CAS  PubMed  Google Scholar 

  • Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., et al. (2004). Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: Evidence for augmentation of a 42-specific γ secretase. Human Molecular Genetics, 13(2), 159–170. doi:10.1093/hmg/ddh019.

    Article  CAS  PubMed  Google Scholar 

  • Janowsky, J. S., Chavez, B., & Orwoll, E. (2000). Sex steroids modify working memory. Journal of Cognitive Neuroscience, 12(3), 407–414. doi:10.1162/089892900562228.

    Article  CAS  PubMed  Google Scholar 

  • Jaworski, T., Kügler, S., & Van Leuven, F. (2010). Modeling of tau-mediated synaptic and neuronal degeneration in Alzheimer’s disease. International Journal of Alzheimer's Disease, 2010, 1–10. doi:10.4061/2010/573138.

    Article  Google Scholar 

  • Ji, Z.-S., Miranda, R. D., Newhouse, Y. M., Weisgraber, K. H., Huang, Y., & Mahley, R. W. (2002). Apolipoprotein E4 potentiates amyloid β peptide-induced lysosomal leakage and apoptosis in neuronal cells. Journal of Biological Chemistry, 277(24), 21821–21828. doi:10.1074/jbc.M112109200.

    Article  CAS  PubMed  Google Scholar 

  • Ji, Z.-S., Müllendorff, K., Cheng, I. H., Miranda, R. D., Huang, Y., & Mahley, R. W. (2006). Reactivity of apolipoprotein E4 and amyloid β peptide lysosomal stability and neurodegeneration. Journal of Biological Chemistry, 281(5), 2683–2692. doi:10.1074/jbc.M506646200.

    Article  CAS  PubMed  Google Scholar 

  • Kanai, M., Shizuka, M., Urakami, K., Matsubara, E., Harigaya, Y., Okamoto, K., et al. (1999). Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer’s disease. Neuroscience Letters, 267(1), 65–68.

    Article  CAS  PubMed  Google Scholar 

  • Katzman, R., & Saitoh, T. (1991). Advances in Alzheimer’s disease. The FASEB Journal, 5(3), 278–286.

    CAS  PubMed  Google Scholar 

  • Kim, J., Basak, J. M., & Holtzman, D. M. (2009). The role of apolipoprotein E in Alzheimer’s disease. Neuron, 63(3), 287–303. doi:10.1016/j.neuron.2009.06.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koh, J., Yang, L. L., & Cotman, C. W. (1990). β-Amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Research, 533(2), 315–320. doi:10.1016/0006-8993(90)91355-K.

    Article  CAS  PubMed  Google Scholar 

  • Kornecook, T. J., McKinney, A. P., Ferguson, M. T., & Dodart, J.-C. (2010). Isoform-specific effects of apolipoprotein E on cognitive performance in targeted-replacement mice overexpressing human APP. Genes, Brain and Behavior, 9(2), 182–192. doi:10.1111/j.1601-183X.2009.00545.x.

    Article  CAS  Google Scholar 

  • Kril, J., Patel, S., Harding, A., & Halliday, G. (2002). Neuron loss from the hippocampus of Alzheimer’s disease exceeds extracellular neurofibrillary tangle formation. Acta Neuropathologica, 103(4), 370–376. doi:10.1007/s00401-001-0477-5.

    Article  PubMed  Google Scholar 

  • LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S., & Frail, D. E. (1994). Isoform-specific binding of apolipoprotein E to beta-amyloid. Journal of Biological Chemistry, 269(38), 23403–23406.

    CAS  PubMed  Google Scholar 

  • LaFerla, F. M., Tinkle, B. T., Bieberich, C. J., Haudenschild, C. C., & Jay, G. (1995). The Alzheimer’s Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nature Genetics, 9(1), 21–30. doi:10.1038/ng0195-21.

    Article  CAS  PubMed  Google Scholar 

  • Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., et al. (2009). Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nature Genetics, 41(10), 1094–1099. doi:10.1038/ng.439.

    Article  CAS  PubMed  Google Scholar 

  • Landén, M., Thorsell, A., Wallin, A., & Blennow, K. (1996). The apolipoprotein E allele epsilon 4 does not correlate with the number of senile plaques or neurofibrillary tangles in patients with Alzheimer’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 61(4), 352–356.

    Article  PubMed  PubMed Central  Google Scholar 

  • Larner, A. J., & Doran, M. (2005). Clinical phenotypic heterogeneity of Alzheimer’s disease associated with mutations of the presenilin-1 gene. Journal of Neurology, 253(2), 139–158. doi:10.1007/s00415-005-0019-5.

    Article  PubMed  CAS  Google Scholar 

  • Lautenschlager, N. T., Cox, K. L., Flicker, L., Foster, J. K., van Bockxmeer, F. M., Xiao, J., et al. (2008). Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease—A randomized trial. JAMA, the Journal of the American Medical Association, 300(9), 1027–1037. doi:10.1001/jama.300.9.1027.

    Article  CAS  PubMed  Google Scholar 

  • Loo, D. T., Copani, A., Pike, C. J., Whittemore, E. R., Walencewicz, A. J., & Cotman, C. W. (1993). Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proceedings of the National Academy of Sciences, 90(17), 7951–7955.

    Article  CAS  Google Scholar 

  • Luine, V. N., Richards, S. T., Wu, V. Y., & Beck, K. D. (1998). Estradiol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters. Hormones and Behavior, 34(2), 149–162. doi:10.1006/hbeh.1998.1473.

    Article  CAS  PubMed  Google Scholar 

  • Lynch, J. R., Tang, W., Wang, H., Vitek, M. P., Bennett, E. R., Sullivan, P. M., et al. (2003). APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. Journal of Biological Chemistry, 278(49), 48529–48533. doi:10.1074/jbc.M306923200.

    Article  CAS  PubMed  Google Scholar 

  • Ma, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994). Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments. Nature, 372(6501), 92–94. doi:10.1038/372092a0.

    Article  CAS  PubMed  Google Scholar 

  • Mahley, R. W. (1988). Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology. Science, 240(4852), 622–630. doi:10.1126/science.3283935.

    Article  CAS  PubMed  Google Scholar 

  • Mahley, R. W., & Rall, S. C., Jr. (2000). Apolipoprotein E: Far more than a lipid transport protein. Annual Review of Genomics and Human Genetics, 1(1), 507–537.

    Article  CAS  PubMed  Google Scholar 

  • Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2006). Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 103(15), 5644–5651. doi:10.1073/pnas.0600549103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2008). Apolipoprotein E: Structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. The Journal of Lipid Research, 50(Suppl.), S183–S188. doi:10.1194/jlr.R800069-JLR200.

    Article  PubMed  CAS  Google Scholar 

  • Mak, K., Yang, F., Vinters, H. V., Frautschy, S. A., & Cole, G. M. (1994). Polyclonals to β-amyloid(1–42) identify most plaque and vascular deposits in Alzheimer cortex, but not striatum. Brain Research, 667(1), 138–142. doi:10.1016/0006-8993(94)91725-6.

    Article  CAS  PubMed  Google Scholar 

  • Mann, D. M., Brown, S. M., Owen, F., Baba, M., & Iwatsubo, T. (1998). Amyloid β protein (Aβ) deposition in dementia with Lewy bodies: Predominance of Aβ42(43) and paucity of Aβ40 compared with sporadic Alzheimer’s disease. Neuropathology and Applied Neurobiology, 24(3), 187–194. doi:10.1046/j.1365-2990.1998.00112.x.

    Article  CAS  PubMed  Google Scholar 

  • Markesbery, W. R. (1997). Oxidative stress hypothesis in Alzheimer’s disease. Free Radical Biology and Medicine, 23(1), 134–147. doi:10.1016/S0891-5849(96)00629-6.

    Article  CAS  PubMed  Google Scholar 

  • Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., & Beyreuther, K. (1985). Amyloid plaque core protein in Alzheimer disease and down syndrome. Proceedings of the National Academy of Sciences, 82(12), 4245–4249.

    Article  CAS  Google Scholar 

  • Matsumoto, K., Pinna, G., Puia, G., Guidotti, A., & Costa, E. (2005). Social isolation stress-induced aggression in mice: A model to study the pharmacology of neurosteroidogenesis. Stress, 8(2), 85–93. doi:10.1080/10253890500159022.

    Article  CAS  PubMed  Google Scholar 

  • Mattson, M. P. (1997). Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiological Reviews, 77(4), 1081–1132.

    CAS  PubMed  Google Scholar 

  • Mattson, M. P., Cheng, B., Davis, D., Bryant, K., Lieberburg, I., & Rydel, R. E. (1992). beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. The Journal of Neuroscience, 12(2), 376–389.

    CAS  PubMed  Google Scholar 

  • Meda, L., Cassatella, M. A., Szendrei, G. I., Otvos, L., Baron, P., Villalba, M., et al. (1995). Activation of microglial cells by β-amyloid protein and interferon-γ. Nature, 374(6523), 647–650. doi:10.1038/374647a0.

    Article  CAS  PubMed  Google Scholar 

  • Miller, A. H., Maletic, V., & Raison, C. L. (2009). Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biological Psychiatry, 65(9), 732–741. doi:10.1016/j.biopsych.2008.11.029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mills, J., & Reiner, P. B. (1999). Regulation of amyloid precursor protein cleavage. Journal of Neurochemistry, 72(2), 443–460. doi:10.1046/j.1471-4159.1999.0720443.x.

    Article  CAS  PubMed  Google Scholar 

  • Mintun, M. A., LaRossa, G. N., Sheline, Y. I., Dence, C. S., Lee, S. Y., Mach, R. H., et al. (2006). [11C]PIB in a nondemented population. Potential antecedent marker of Alzheimer disease. Neurology, 67(3), 446–452. doi:10.1212/01.wnl.0000228230.26044.a4.

    Article  CAS  PubMed  Google Scholar 

  • Miyata, M., & Smith, J. D. (1996). Apolipoprotein E allele–specific antioxidant activity and effects on cytotoxicity by oxidative insults and β–amyloid peptides. Nature Genetics, 14(1), 55–61. doi:10.1038/ng0996-55.

    Article  CAS  PubMed  Google Scholar 

  • Morsch, R., Simon, W., & Coleman, P. D. (1999). Neurons may live for decades with neurofibrillary tangles. Journal of Neuropathology and Experimental Neurology, 58(2), 188–197.

    Article  CAS  PubMed  Google Scholar 

  • Nagy, Z. S., Esiri, M. M., Jobst, K. A., Johnston, C., Litchfield, S., Sim, E., et al. (1995). Influence of the apolipoprotein E genotype on amyloid deposition and neurofibrillary tangle formation in Alzheimer’s disease. Neuroscience, 69(3), 757–761. doi:10.1016/0306-4522(95)00331-C.

    Article  CAS  PubMed  Google Scholar 

  • Negash, S., Greenwood, P. M., Sunderland, T., Parasuraman, R., Geda, Y. E., Knopman, D. S., et al. (2009). The influence of Apolipoprotein E genotype on visuospatial attention dissipates after age 80. Neuropsychology, 23(1), 81–89. doi:10.1037/a0014014.

    Article  PubMed  PubMed Central  Google Scholar 

  • Neve, R. L., & Robakis, N. K. (1998). Alzheimer’s disease: A re-examination of the amyloid hypothesis. Trends in Neurosciences, 21(1), 15–19. doi:10.1016/S0166-2236(97)01168-5.

    Article  CAS  PubMed  Google Scholar 

  • Nichol, K., Deeny, S. P., Seif, J., Camaclang, K., & Cotman, C. W. (2009). Exercise improves cognition and hippocampal plasticity in APOE ε4 mice. Alzheimer’s and Dementia, 5(4), 287–294. doi:10.1016/j.jalz.2009.02.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohm, T. G., Kirca, M., Bohl, J., Scharnagl, H., Groβ, W., & März, W. (1995). Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation. Neuroscience, 66(3), 583–587. doi:10.1016/0306-4522(94)00596-W.

    Article  CAS  PubMed  Google Scholar 

  • Olgiati, P., Politis, A. M., Papadimitriou, G. N., De Ronchi, D., & Serretti, A. (2011). Genetics of late-onset alzheimer’s disease: Update from the Alzgene database and analysis of shared pathways. International Journal of Alzheimer’s Disease, 2011, 832379. doi:10.4061/2011/832379.

    Google Scholar 

  • Olsen, R. H. J., Agam, M., Davis, M. J., & Raber, J. (2012). ApoE isoform-dependent deficits in extinction of contextual fear conditioning. Genes, Brain and Behavior, 11(7), 806–812. doi:10.1111/j.1601-183X.2012.00833.x.

    Article  CAS  Google Scholar 

  • Packard, C. J., Westendorp, R. G. J., Stott, D. J., Caslake, M. J., Murray, H. M., Shepherd, J., et al. (2007). Association between apolipoprotein E4 and cognitive decline in elderly adults. Journal of the American Geriatrics Society, 55(11), 1777–1785. doi:10.1111/j.1532-5415.2007.01415.x.

    Article  PubMed  Google Scholar 

  • Pearson, H. A., & Peers, C. (2006). Physiological roles for amyloid β peptides. The Journal of Physiology, 575(1), 5–10. doi:10.1113/jphysiol.2006.111203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pfankuch, T., Rizk, A., Olsen, R., Poage, C., & Raber, J. (2005). Role of circulating androgen levels in effects of apoE4 on cognitive function. Brain Research, 1053(1–2), 88–96. doi:10.1016/j.brainres.2005.06.028.

    Article  CAS  PubMed  Google Scholar 

  • Plant, L. D., Boyle, J. P., Smith, I. F., Peers, C., & Pearson, H. A. (2003). The production of amyloid β peptide is a critical requirement for the viability of central neurons. The Journal of Neuroscience, 23(13), 5531–5535.

    CAS  PubMed  Google Scholar 

  • Price, J. L., & Morris, J. C. (1999). Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Annals of Neurology, 45(3), 358–368.

    Article  CAS  PubMed  Google Scholar 

  • Raber, J., Bongers, G., LeFevour, A., Buttini, M., & Mucke, L. (2002). Androgens protect against apolipoprotein E4-induced cognitive deficits. The Journal of Neuroscience, 22(12), 5204–5209.

    CAS  PubMed  Google Scholar 

  • Raber, J., Wong, D., Buttini, M., Orth, M., Bellosta, S., Pitas, R. E., et al. (1998). Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: Increased susceptibility of females. Proceedings of the National Academy of Sciences, 95(18), 10914–10919.

    Article  CAS  Google Scholar 

  • Raber, J., Wong, D., Yu, G.-Q., Buttini, M., Mahley, R. W., Pitas, R. E., et al. (2000). Alzheimer’s disease: Apolipoprotein E and cognitive performance. Nature, 404(6776), 352–354. doi:10.1038/35006165.

    Article  CAS  PubMed  Google Scholar 

  • Reverte, I., Klein, A. B., Ratner, C., Domingo, J. L., & Colomina, M. T. (2012). Behavioral phenotype and BDNF differences related to apoE isoforms and sex in young transgenic mice. Experimental Neurology, 237(1), 116–125. doi:10.1016/j.expneurol.2012.06.015.

    Article  CAS  PubMed  Google Scholar 

  • Reyland, M. E., Gwynne, J. T., Forgez, P., Prack, M. M., & Williams, D. L. (1991). Expression of the human apolipoprotein E gene suppresses steroidogenesis in mouse Y1 adrenal cells. Proceedings of the National Academy of Sciences, 88(6), 2375–2379.

    Article  CAS  Google Scholar 

  • Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., et al. (2007). Reducing endogenous tau ameliorates amyloid ß-induced deficits in an Alzheimer’s disease mouse model. Science, 316(5825), 750–754. doi:10.1126/science.1141736.

    Article  CAS  PubMed  Google Scholar 

  • Robertson, J., Curley, J., Kaye, J., Quinn, J., Pfankuch, T., & Raber, J. (2005). apoE isoforms and measures of anxiety in probable AD patients and Apoe−/− mice. Neurobiology of Aging, 26(5), 637–643. doi:10.1016/j.neurobiolaging.2004.06.003.

    Article  CAS  PubMed  Google Scholar 

  • Roßner, S., Ueberham, U., Schliebs, R., Regino Perez-Polo, J., & Bigl, V. (1998). The regulation of amyloid precursor protein metabolism by cholinergic mechanisms and neurotrophin receptor signaling. Progress in Neurobiology, 56(5), 541–569. doi:10.1016/S0301-0082(98)00044-6.

    Article  PubMed  Google Scholar 

  • Rowe, C. C., Ng, S., Ackermann, U., Gong, S. J., Pike, K., Savage, G., et al. (2007). Imaging beta-amyloid burden in aging and dementia. Neurology, 68(20), 1718–1725.

    Article  CAS  PubMed  Google Scholar 

  • Sadowski, M. J., Pankiewicz, J., Scholtzova, H., Mehta, P. D., Prelli, F., Quartermain, D., et al. (2006). Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer’s disease. Proceedings of the National Academy of Sciences, 103(49), 18787–18792. doi:10.1073/pnas.0604011103.

    Article  CAS  Google Scholar 

  • Salomon-Zimri, S., Boehm-Cagan, A., Liraz, O., & Michaelson, D. M. (2014). Hippocampus-related cognitive impairments in young apoE4 targeted replacement mice. Neurodegenerative Diseases, 13, 86–92. doi:10.1159/000354777.

    Article  CAS  PubMed  Google Scholar 

  • Saunders, A. M., Strittmatter, W. J., Schmechel, D., St. George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., et al. (1993). Association of apolipoprotein E allele Ε4 with late‐onset familial and sporadic Alzheimer’s disease. Neurology, 43(8), 1467–1472.

    Article  CAS  PubMed  Google Scholar 

  • Schmechel, D. E., Saunders, A. M., Strittmatter, W. J., Crain, B. J., Hulette, C. M., Joo, S. H., et al. (1993). Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset alzheimer disease. Proceedings of the National Academy of Sciences, 90(20), 9649–9653.

    Google Scholar 

  • Selkoe, D. J. (1998). The cell biology of β-amyloid precursor protein and presenilin in Alzheimer’s disease. Trends in Cell Biology, 8(11), 447–453. doi:10.1016/S0962-8924(98)01363-4.

    Article  CAS  PubMed  Google Scholar 

  • Seubert, P., Oltersdorf, T., Lee, M. G., Barbour, R., Blomquist, C., Davis, D. L., et al. (1993). Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide. Nature, 361(6409), 260–263. doi:10.1038/361260a0.

    Article  CAS  PubMed  Google Scholar 

  • Seubert, P., Vigo-Pelfrey, C., Esch, F., Lee, M., Dovey, H., Davis, D., et al. (1992). Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature, 359(6393), 325–327. doi:10.1038/359325a0.

    Article  CAS  PubMed  Google Scholar 

  • Shore, V. G., & Shore, B. (1973). Heterogeneity of human plasma very low density lipoproteins. Separation of species differing in protein components. Biochemistry, 12(3), 502–507. doi:10.1021/bi00727a022.

    Article  CAS  PubMed  Google Scholar 

  • Siegel, J. A., Haley, G. E., & Raber, J. (2012). Apolipoprotein E isoform-dependent effects on anxiety and cognition in female TR mice. Neurobiology of Aging, 33(2), 345–358. doi:10.1016/j.neurobiolaging.2010.03.002.

    Article  CAS  PubMed  Google Scholar 

  • Sisodia, S. S. (1992). Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proceedings of the National Academy of Sciences, 89(13), 6075–6079.

    Article  CAS  Google Scholar 

  • Sisodia, S. S., Koo, E. H., Beyreuther, K., Unterbeck, A., & Price, D. L. (1990). Evidence that beta-amyloid protein in Alzheimer’s disease is not derived by normal processing. Science, 248(4954), 492–495. doi:10.1126/science.1691865.

    Article  CAS  PubMed  Google Scholar 

  • Smith, G. E., Bohac, D., Waring, S., Kokmen, E., Tangalos, E., Ivnik, R., et al. (1998). Apolipoprotein E genotype influences cognitive “phenotype” in patients with Alzheimer’s disease but not in healthy control subjects. Neurology, 50(2), 355–362.

    Article  CAS  PubMed  Google Scholar 

  • Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., et al. (1993). Apolipoprotein E: High-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences, 90(5), 1977–1981.

    Article  CAS  Google Scholar 

  • Strooper, B. D., & Annaert, W. (2000). Proteolytic processing and cell biological functions of the amyloid precursor protein. Journal of Cell Science, 113(11), 1857–1870.

    PubMed  Google Scholar 

  • Sullivan, P., Mace, B., Maeda, N., & Schmechel, D. (2004). Marked regional differences of brain human apolipoprotein e expression in targeted replacement mice. Neuroscience, 124(4), 725–733. doi:10.1016/j.neuroscience.2003.10.011.

    Article  CAS  PubMed  Google Scholar 

  • Sullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., et al. (1997). Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. Journal of Biological Chemistry, 272(29), 17972–17980. doi:10.1074/jbc.272.29.17972.

    Article  CAS  PubMed  Google Scholar 

  • Takashima, A. (2008). Hyperphosphorylated tau is a cause of neuronal dysfunction in tauopathy. Journal of Alzheimer's Disease, 14(4), 371–375.

    PubMed  Google Scholar 

  • Tamaoka, A., Sawamura, N., Fukushima, T., Shoji, S., Matsubara, E., Shoji, M., et al. (1997). Amyloid β protein 42(43) in cerebrospinal fluid of patients with Alzheimer’s disease. Journal of the Neurological Sciences, 148(1), 41–45. doi:10.1016/S0022-510X(96)00314-0.

    Article  CAS  PubMed  Google Scholar 

  • Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., et al. (1991). Physical basis of cognitive alterations in Alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment. Annals of Neurology, 30(4), 572–580. doi:10.1002/ana.410300410.

    Article  CAS  PubMed  Google Scholar 

  • Tesseur, I., Van Dorpe, J., Spittaels, K., Van den Haute, C., Moechars, D., & Van Leuven, F. (2000). Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. The American Journal of Pathology, 156(3), 951–964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thal, D. R., Capetillo-Zarate, E., Del Tredici, K., & Braak, H. (2006). The development of amyloid beta protein deposits in the aged brain. Science of Aging Knowledge Environment, 2006(6), re1. doi:10.1126/sageke.2006.6.re1.

    Article  PubMed  Google Scholar 

  • Thal, D. R., Rüb, U., Orantes, M., & Braak, H. (2002). Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology, 58(12), 1791–1800. doi:10.1212/WNL.58.12.1791.

    Article  PubMed  Google Scholar 

  • Thal, D. R., Rub, U., Schultz, C., Sassin, I., Ghebremedhin, E., Tredici, K. D., et al. (2000). Sequence of (A(beta))-protein deposition in the human medial temporal lobe. Journal of Neuropathology and Experimental Neurology, 59(8), 733–748.

    Article  CAS  PubMed  Google Scholar 

  • Tokuda, T., Calero, M., Matsubara, E., Vidal, R., Kumar, A., Permanne, B., et al. (2000). Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer’s amyloid beta peptides. Biochemical Journal, 348(Pt 2), 359–365.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Travert, C., Forfana, M., Carreau, S., & Le Goff, D. (2000). Rat Leydig cells use apolipoprotein E depleted high density lipoprotein to regulate testosterone production. Molecular and Cellular Biochemistry, 213(1), 51–59.

    Article  CAS  PubMed  Google Scholar 

  • Van Haaren, F., van Hest, A., & Heinsbroek, R. P. W. (1990). Behavioral differences between male and female rats: Effects of gonadal hormones on learning and memory. Neuroscience & Biobehavioral Reviews, 14(1), 23–33. doi:10.1016/S0149-7634(05)80157-5.

    Article  Google Scholar 

  • Van Meer, P., Acevedo, S., & Raber, J. (2007). Impairments in spatial memory retention of GFAP-apoE4 female mice. Behavioural Brain Research, 176(2), 372–375. doi:10.1016/j.bbr.2006.10.024.

    Article  PubMed  CAS  Google Scholar 

  • Villasana, L., Acevedo, S., Poage, C., & Raber, J. (2006). Sex-and APOE isoform-dependent effects of radiation on cognitive function. Radiation Research, 166(6), 883–891.

    Article  CAS  PubMed  Google Scholar 

  • Villasana, L. E., Benice, T. S., & Raber, J. (2011). Long-term effects of 56Fe irradiation on spatial memory of mice: Role of sex and apolipoprotein E isoform. International Journal of Radiation Oncology, Biology, Physics, 80(2), 567–573. doi:10.1016/j.ijrobp.2010.12.034.

    Article  CAS  PubMed  Google Scholar 

  • Weiss, J. H., Pike, C. J., & Cotman, C. W. (1994). Rapid communication: Ca2+ channel blockers attenuate β-amyloid peptide toxicity to cortical neurons in culture. Journal of Neurochemistry, 62(1), 372–375. doi:10.1046/j.1471-4159.1994.62010372.x.

    Article  CAS  PubMed  Google Scholar 

  • Xu, Q., Bernardo, A., Walker, D., Kanegawa, T., Mahley, R. W., & Huang, Y. (2006). Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. The Journal of Neuroscience, 26(19), 4985–4994. doi:10.1523/JNEUROSCI.5476-05.2006.

    Article  CAS  PubMed  Google Scholar 

  • Xu, P.-T., Schmechel, D., Rothrock-Christian, T., Burkhart, D. S., Qiu, H.-L., Popko, B., et al. (1996). Human apolipoprotein E2, E3, and E4 isoform-specific transgenic mice: Human-like pattern of glial and neuronal immunoreactivity in central nervous system not observed in wild-type mice. Neurobiology of Disease, 3(3), 229–245. doi:10.1006/nbdi.1996.0023.

    Article  CAS  PubMed  Google Scholar 

  • Xu, Q., Walker, D., Bernardo, A., Brodbeck, J., Balestra, M. E., & Huang, Y. (2008). Intron-3 retention/splicing controls neuronal expression of apolipoprotein E in the CNS. The Journal of Neuroscience, 28(6), 1452–1459. doi:10.1523/JNEUROSCI.3253-07.2008.

    Article  CAS  PubMed  Google Scholar 

  • Ye, S., Huang, Y., Müllendorff, K., Dong, L., Giedt, G., Meng, E. C., et al. (2005). Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target. Proceedings of the National Academy of Sciences of the United States of America, 102(51), 18700–18705. doi:10.1073/pnas.0508693102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou, Y., Elkins, P. D., Howell, L. A., Ryan, D. H., & Harris, R. B. S. (1998). Apolipoprotein-E deficiency results in an altered stress responsiveness in addition to an impaired spatial memory in young mice. Brain Research, 788(1–2), 151–159. doi:10.1016/S0006-8993(97)01533-3.

    Article  CAS  PubMed  Google Scholar 

  • Zofkova, I., Zajickova, K., Hill, M., & Horinek, A. (2002). Apolipoprotein E gene determines serum testosterone and dehydroepiandrosterone levels in postmenopausal women. European Journal of Endocrinology, 147(4), 503–506. doi:10.1530/eje.0.1470503.

    Article  CAS  PubMed  Google Scholar 

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  1. School of Psychology and Speech Pathology, Curtin University, Perth, WA, Australia

    Matthew A. Albrecht & Jonathan K. Foster

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    Matthew A. Albrecht

  3. Neurosciences Unit, Health Department of WA, GPO Box U1987, Perth, WA, 6844, Australia

    Jonathan K. Foster

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    Jonathan C. Gewirtz

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Albrecht, M.A., Foster, J.K. (2016). Genetic Models of Alzheimer’s Disease: The Influence of Apolipoprotein E allele Isoforms on Behaviour in Laboratory Animals. In: Gewirtz, J., Kim, YK. (eds) Animal Models of Behavior Genetics. Advances in Behavior Genetics. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3777-6_7

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