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APP Transgenic Mice: Their Use and Limitations

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Abstract

Alzheimer’s disease is the most widespread form of dementia. Its histopathological hallmarks include vascular and extracellular β-amyloid (Aβ) deposition and intraneuronal neurofibrillary tangles (NFTs). Gradual decline of cognitive functions linked to progressive synaptic loss makes patients unable to store new information in the earlier stages of the pathology, later becoming completely dependent because they are unable to do even elementary daily life actions. Although more than a hundred years have passed since Alois Alzheimer described the first case of AD, and despite many years of intense research, there are still many crucial points to be discovered in the neuropathological pathway. The development of transgenic mouse models engineered with overexpression of the amyloid precursor protein carrying familial AD mutations has been extremely useful. Transgenic mice present the hallmarks of the pathology, and histological and behavioural examination supports the amyloid hypothesis. As in human AD, extracellular Aβ deposits surrounded by activated astrocytes and microglia are typical features, together with synaptic and cognitive defects. Although animal models have been widely used, they are still being continuously developed in order to recapitulate some missing aspects of the disease. For instance, AD therapeutic agents tested in transgenic mice gave encouraging results which, however, were very disappointing in clinical trials. Neuronal cell death and NFTs typical of AD are much harder to replicate in these mice, which thus offer a fundamental but still imperfect tool for understanding and solving dementia pathology.

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References

  • Abraham, W. C., & Williams, J. M. (2008). LTP maintenance and its protein synthesis-dependence. Neurobiology of Learning and Memory, 89, 260–268.

    PubMed  CAS  Google Scholar 

  • Aho, L., Pikkarainen, M., Hiltunen, M., et al. (2010). Immunohistochemical Visualization of Amyloid-beta Protein Precursor and Amyloid-beta in Extra- and Intracellular Compartments in the Human Brain. Journal of Alzheimer’s Disease, 20, 1015–1028.

    PubMed  CAS  Google Scholar 

  • Akiyama, H., Barger, S., Barnum, S., et al. (2000). Inflammation and Alzheimer’s disease. Neurobiology of Aging, 21, 383–421.

    PubMed  CAS  Google Scholar 

  • Almeida, C. G., Tampellini, D., Takahashi, R. H., et al. (2005). Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GLR1 in synapses. Neurobiology of Disease, 20, 187–198.

    PubMed  CAS  Google Scholar 

  • Arendash, G. W., & King, D. L. (2002). Intra- and intertask relationships in a behavioral test battery given to Tg2576 transgenic mice and controls. Physiology & Behavior, 75, 643–652.

    CAS  Google Scholar 

  • Arendash, G. W., King, D. L., Gordon, M. N., et al. (2001). Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes. Brain Research, 891, 42–53.

    PubMed  CAS  Google Scholar 

  • Bacskai, B. J., Klunk, W. E., Mathis, C. A., et al. (2002). Imaging amyloid-beta deposits in vivo. Journal of Cerebral Blood Flow and Metabolism, 22, 1035–1041.

    PubMed  CAS  Google Scholar 

  • Badea, A., Johnson, G. A., & Jankowsky, J. L. (2010). Remote sites of structural atrophy predict later amyloid formation in a mouse model of Alzheimer’s disease. Neuroimage, 50, 416–427.

    PubMed  Google Scholar 

  • Balducci, C., Beeg, M., Stravalaci, M., et al. (2010a). Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proceedings of the National Academy of Sciences of the United States of America, 107, 2295–2300.

    PubMed  CAS  Google Scholar 

  • Balducci, C., Tonini, R., Zianni, E., et al. (2010b). Cognitive deficits associated with alteration of synaptic metaplasticity precede plaque deposition in APP23 transgenic mice. Journal of Alzheimer’s Disease. (in press).

  • Benveniste, H., Einstein, G., Kim, K. R., et al. (1999). Detection of neuritic plaques in Alzheimer’s disease by magnetic resonance microscopy. Proceedings of the National Academy of Sciences of the United States of America, 96, 14079–14084.

    PubMed  CAS  Google Scholar 

  • Benveniste, H., Ma, Y., Dhawan, J., et al. (2007). Anatomical and functional phenotyping of mice models of Alzheimer’s disease by MR microscopy. Annals of the New York Academy of Sciences, 1097, 12–29.

    PubMed  CAS  Google Scholar 

  • Bereiter-Hahn, J., & Voth, M. (1994). Dynamics of mitochondria in living cells: Shape changes, dislocations, fusion, and fission of mitochondria. Microscopy Research and Technique, 27, 198–219.

    PubMed  CAS  Google Scholar 

  • Billings, L. M., Oddo, S., Green, K. N., et al. (2005). Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron, 45(5), 675–688.

    PubMed  CAS  Google Scholar 

  • Blasko, I., Marx, F., Steiner, E., et al. (1999). TNFalpha plus IFNgamma induce the production of Alzheimer beta-amyloid peptides and decrease the secretion of APPs. The FASEB Journal, 13, 63–68.

    PubMed  CAS  Google Scholar 

  • Blennow, K., & Zetterberg, H. (2009). Cerebrospinal fluid biomarkers for Alzheimer’s disease. Journal of Alzheimer’s Disease, 18, 413–417.

    PubMed  CAS  Google Scholar 

  • Blurton-Jones, M., & Laferla, F. M. (2006). Pathways by which Abeta facilitates tau pathology. Current Alzheimer Research, 3, 437–448.

    PubMed  CAS  Google Scholar 

  • Bolmont, T., Clavaguera, F., Meyer-Luehmann, M., et al. (2007). Induction of tau pathology by intracerebral infusion of amyloid-beta -containing brain extract and by amyloid-beta deposition in APP x Tau transgenic mice. American Journal of Pathology, 171, 2012–2020.

    PubMed  CAS  Google Scholar 

  • Bolmont, T., Haiss, F., Eicke, D., et al. (2008). Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. Journal of Neuroscience, 28, 4283–4292.

    PubMed  CAS  Google Scholar 

  • Boncristiano, S., Calhoun, M. E., Howard, V., et al. (2005). Neocortical synaptic bouton number is maintained despite robust amyloid deposition in APP23 transgenic mice. Neurobiology of Aging, 26, 607–613.

    PubMed  CAS  Google Scholar 

  • Borchelt, D. R., Ratovitski, T., van Lare, J., et al. (1997). Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron, 19, 939–945.

    PubMed  CAS  Google Scholar 

  • Borchelt, D. R., Thinakaran, G., Eckman, C. B., et al. (1996). Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1–42/1–40 ratio in vitro and in vivo. Neuron, 17, 1005–1013.

    PubMed  CAS  Google Scholar 

  • Brody, D. L., & Holtzman, D. M. (2008). Active and passive immunotherapy for neurodegenerative disorders. Annual Review of Neuroscience, 31, 175–193.

    PubMed  CAS  Google Scholar 

  • Buxbaum, J. D., Christensen, J. L., Ruefli, A. A., et al. (1993). Expression of APP in brains of transgenic mice containing the entire human APP gene. Biochemical and Biophysical Research Communications, 197, 639–645.

    PubMed  CAS  Google Scholar 

  • Buxbaum, J. D., Oishi, M., Chen, H. I., et al. (1992). Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proceedings of the National Academy of Sciences of the United States of America, 89, 10075–10078.

    PubMed  CAS  Google Scholar 

  • Calhoun, M. E., Wiederhold, K. H., Abramowski, D., et al. (1998). Neuron loss in APP transgenic mice. Nature, 395, 755–756.

    PubMed  CAS  Google Scholar 

  • Casas, C., Sergeant, N., Itier, J. M., et al. (2004). Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. American Journal of Pathology, 165, 1289–1300.

    PubMed  CAS  Google Scholar 

  • Caspersen, C., Wang, N., Yao, J., et al. (2005). Mitochondrial Abeta: A potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. The FASEB Journal, 19, 2040–2041.

    PubMed  CAS  Google Scholar 

  • Chapman, P. F., White, G. L., Jones, M. W., et al. (1999). Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nature Neuroscience, 2, 271–276.

    PubMed  CAS  Google Scholar 

  • Chartier-Harlin, M. C., Crawford, F., Houlden, H., et al. (1991). Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature, 353, 844–846.

    PubMed  CAS  Google Scholar 

  • Chen, W. S., & Bear, M. F. (2007). Activity-dependent regulation of NR2B translation contributes to metaplasticity in mouse visual cortex. Neuropharmacology, 52, 200–214.

    PubMed  CAS  Google Scholar 

  • Chen, G., Chen, K. S., Knox, J., et al. (2000). A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer’s disease. Nature, 408, 975–979.

    PubMed  CAS  Google Scholar 

  • Cheng, I. H., Palop, J. J., Esposito, L. A., et al. (2004). Aggressive amyloidosis in mice expressing human amyloid peptides with the Arctic mutation. Nature Medicine, 10, 1190–1192.

    PubMed  CAS  Google Scholar 

  • Cheng, I. H., Scearce-Levie, K., Legleiter, J., et al. (2007). Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. The Journal of Biological Chemistry, 282, 23818–23828.

    PubMed  CAS  Google Scholar 

  • Chin, J., Palop, J. J., Puolivali, J., et al. (2005). Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer’s disease. Journal of Neuroscience, 25, 9694–9703.

    PubMed  CAS  Google Scholar 

  • Chishti, M. A., Yang, D. S., Janus, C., et al. (2001). Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. The Journal of Biological Chemistry, 276, 21562–21570.

    PubMed  CAS  Google Scholar 

  • Choi, J. K., Dedeoglu, A., & Jenkins, B. G. (2007). Application of MRS to mouse models of neurodegenerative illness. NMR in Biomedicine, 20, 216–237.

    PubMed  Google Scholar 

  • Chong, Y. (1997). Effect of a carboxy-terminal fragment of the Alzheimer’s amyloid precursor protein on expression of proinflammatory cytokines in rat glial cells. Life Science, 61, 2323–2333.

    CAS  Google Scholar 

  • Chui, D. H., Shirotani, K., Tanahashi, H., et al. (1998). Both N-terminal and C-terminal fragments of presenilin 1 colocalize with neurofibrillary tangles in neurons and dystrophic neurites of senile plaques in Alzheimer’s disease. Journal of Neuroscience Research, 53, 99–106.

    PubMed  CAS  Google Scholar 

  • Cleary, J. P., Walsh, D. M., Hofmeister, J. J., et al. (2005). Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nature Neuroscience, 8, 79–84.

    PubMed  CAS  Google Scholar 

  • Comery, T. A., Martone, R. L., Aschmies, S., et al. (2005). Acute gamma-secretase inhibition improves contextual fear conditioning in the Tg2576 mouse model of Alzheimer’s disease. Journal of Neuroscience, 25, 8898–8902.

    PubMed  CAS  Google Scholar 

  • Cooke, S. F., & Bliss, T. V. (2006). Plasticity in the human central nervous system. Brain, 129, 1659–1673.

    PubMed  CAS  Google Scholar 

  • Corcoran, K. A., Lu, Y., Turner, R. S., & Maren, S. (2002). Overexpression of hAPPswe impairs rewarded alternation and contextual fear conditioning in a transgenic mouse model of Alzheimer’s disease. Learning & Memory, 9, 243–252.

    Google Scholar 

  • Cruz, J. C., Kim, D., Moy, L. Y., et al. (2006). p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. Journal of Neuroscience, 26(41), 10536–10541.

    PubMed  CAS  Google Scholar 

  • Cummings, J. L. (2007). Treatment of Alzheimer’s disease: The role of symptomatic agents in an era of disease-modifying therapies. Reviews in Neurological Diseases, 4, 57–62.

    PubMed  Google Scholar 

  • DeKosky, S. T., & Scheff, S. W. (1990). Synapse loss in frontal cortex biopsies in Alzheimer’s disease: Correlation with cognitive severity. Annals of Neurology, 27, 457–464.

    PubMed  CAS  Google Scholar 

  • Del Bo, R., Angeretti, N., Lucca, E., et al. (1995). Reciprocal control of inflammatory cytokines, IL-1 and IL-6, and beta-amyloid production in cultures. Neuroscience Letters, 188, 70–74.

    PubMed  CAS  Google Scholar 

  • Delatour, B., Guegan, M., Volk, A., & Dhenain, M. (2006). In vivo MRI and histological evaluation of brain atrophy in APP/PS1 transgenic mice. Neurobiology of Aging, 27, 835–847.

    PubMed  CAS  Google Scholar 

  • Dere, E., Huston, J. P., & De Souza Silva, M. A. (2007). The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neuroscience and Biobehavioral Reviews, 31, 673–704.

    PubMed  CAS  Google Scholar 

  • Dhenain, M., Privat, N., Duyckaerts, C., et al. (2002). Senile plaques do not induce susceptibility effects in T2*-weighted MR microscopic images. NMR in Biomedicine, 15, 197–203.

    PubMed  Google Scholar 

  • Dinamarca, M. C., Arrazola, M., Toledo, E., et al. (2008). Release of acetylcholinesterase (AChE) from beta-amyloid plaques assemblies improves the spatial memory impairments in APP-transgenic mice. Chemico-biological Interactions, 175, 142–149.

    PubMed  CAS  Google Scholar 

  • Dodart, J. C., Bales, K. R., Gannon, K. S., et al. (2002). Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nature Neuroscience, 5, 452–457.

    PubMed  CAS  Google Scholar 

  • Dodart, J. C., Mathis, C., Bales, K. R., et al. (2000a). Behavioral deficits in APP(V717F) transgenic mice deficient for the apolipoprotein E gene. Neuroreport, 11, 603–607.

    PubMed  CAS  Google Scholar 

  • Dodart, J. C., Mathis, C., Saura, J., et al. (2000b). Neuroanatomical abnormalities in behaviorally characterized APP(V717F) transgenic mice. Neurobiology of Diseases, 7, 71–85.

    CAS  Google Scholar 

  • Dodart, J. C., Meziane, H., Mathis, C., et al. (1999). Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Behavioral Neuroscience, 113, 982–990.

    PubMed  CAS  Google Scholar 

  • Dong, J., Revilla-Sanchez, R., Moss, S., et al. (2010) Multiphoton in vivo imaging of amyloid in animal models of Alzheimer’s disease. Neuropharmacology, 1–8.

  • Du, H., Guo, L., Fang, F., et al. (2008). Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nature Medicine, 14, 1097–1105.

    PubMed  CAS  Google Scholar 

  • Duff, K., Eckman, C., Zehr, C., et al. (1996). Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature, 383, 710–713.

    PubMed  CAS  Google Scholar 

  • Duff, K., & Suleman, F. (2004). Transgenic mouse models of Alzheimer’s disease: How useful have they been for therapeutic development? Briefings in Functional Genomics & Proteomics, 3, 47–59.

    CAS  Google Scholar 

  • Esh, C., Patton, L., Kalback, W., et al. (2005). Altered APP processing in PDAPP (Val717–> Phe) transgenic mice yields extended-length Abeta peptides. Biochemistry, 44, 13807–13819.

    PubMed  CAS  Google Scholar 

  • Espana, J., Gimenez-Llort, L., Valero, J., et al. (2010). Intraneuronal beta-amyloid accumulation in the amygdala enhances fear and anxiety in Alzheimer’s disease transgenic mice. Biological Psychiatry, 67, 513–521.

    PubMed  CAS  Google Scholar 

  • Fagan, A. M., Mintun, M. A., Mach, R. H., et al. (2006). Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Annals of Neurology, 59, 512–519.

    PubMed  CAS  Google Scholar 

  • Falangola, M. F., Lee, S. P., Nixon, R. A., et al. (2005). Histological co-localization of iron in Abeta plaques of PS/APP transgenic mice. Neurochemical Research, 30, 201–205.

    PubMed  CAS  Google Scholar 

  • Forloni, G., Demicheli, F., Giorgi, S., et al. (1992). Expression of amyloid precursor protein mRNAs in endothelial, neuronal and glial cells: Modulation by interleukin-1. Brain Research. Molecular Brain Research, 16(1–2), 128–134.

    PubMed  CAS  Google Scholar 

  • Forloni, G., Lucca, E., Angeretti, N., et al. (1997). Amidation of beta-amyloid peptide strongly reduced the amyloidogenic activity without alteration of the neurotoxicity. Journal of Neurochemistry, 69(5), 2048–2054.

    PubMed  CAS  Google Scholar 

  • Frisoni, G. B., Fox, N. C., Jack, C. R., et al. (2010). The clinical use of structural MRI in Alzheimer disease. Nature Reviews. Neurology, 6, 67–77.

    PubMed  Google Scholar 

  • Funato, H., Enya, M., Yoshimura, M., et al. (1999). Presence of sodium dodecyl sulfate-stable amyloid beta-protein dimers in the hippocampus CA1 not exhibiting neurofibrillary tangle formation. American Journal of Pathology, 155, 23–28.

    PubMed  CAS  Google Scholar 

  • Games, D., Adams, D., Alessandrini, R., et al. (1995). Alzheimer-type neuropathology in transgenic mice over-expressing V717F beta-amyloid precursor protein. Nature, 373, 523–527.

    PubMed  CAS  Google Scholar 

  • Garcia-Alloza, M., & Bacskai, B. J. (2004). Techniques for brain imaging in vivo. Neuromolecular Medicine, 6, 65–78.

    PubMed  CAS  Google Scholar 

  • Garcia-Alloza, M., Robbins, E. M., Zhang-Nunes, S. X., et al. (2006). Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiology of Diseases, 24, 516–524.

    CAS  Google Scholar 

  • Gilman, S., Koller, M., Black, R. S., et al. (2005). Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 64, 1553–1562.

    PubMed  CAS  Google Scholar 

  • Gitter, B. D., Cox, L. M., Rydel, R. E., et al. (1995). Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells. Proceedings of the National Academy of Sciences of the United States of America, 92, 10738–10741.

    PubMed  CAS  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, 885–890.

    PubMed  CAS  Google Scholar 

  • Goate, A., Chartier-Harlin, M. C., Mullan, M., et al. (1991). Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature, 349, 704–706.

    PubMed  CAS  Google Scholar 

  • Gonzalez-Lima, F., Berndt, J. D., Valla, J. E., et al. (2001). Reduced corpus callosum, fornix and hippocampus in PDAPP transgenic mouse model of Alzheimer’s disease. Neuroreport, 12, 2375–2379.

    PubMed  CAS  Google Scholar 

  • Gordon, M. N., King, D. L., Diamond, D. M., et al. (2001). Correlation between cognitive deficits and Abeta deposits in transgenic APP+PS1 mice. Neurobiology of Aging, 22, 377–385.

    PubMed  CAS  Google Scholar 

  • Gotz, J., Chen, F., van Dorpe, J., et al. (2001). Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science, 293, 1491–1495.

    PubMed  CAS  Google Scholar 

  • Gotz, J., Schild, A., Hoerndli, F., et al. (2004). Amyloid-induced neurofibrillary tangle formation in Alzheimer’s disease: Insight from transgenic mouse and tissue-culture models. International Journal of Developmental Neuroscience, 22, 453–465.

    PubMed  Google Scholar 

  • Gouras, G. K., Tsai, J., Naslund, J., et al. (2000). Intraneuronal Abeta42 accumulation in human brain. American Journal of Pathology, 156, 15–20.

    PubMed  CAS  Google Scholar 

  • Greco, S. J., Bryan, K. J., Sarkar, S., et al. (2010). Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer’s disease. Journal of Alzheimer’s Disease, 19, 1155–1167.

    PubMed  CAS  Google Scholar 

  • Grueninger, F., Bohrmann, B., & Czech, C. (2010). Phosphorylation of Tau at S422 is enhanced by Abeta in TauPS2APP triple transgenic mice. Neurobiology of Diseases, 37(2), 294–306.

    CAS  Google Scholar 

  • Grutzendler, J., Helmin, K., Tsai, J., et al. (2007). Various dendritic abnormalities are associated with fibrillar amyloid deposits in Alzheimer’s disease. Annals of the New York Academy of Sciences, 1097, 30–39.

    PubMed  Google Scholar 

  • Guo, J. T., Yu, J., Grass, D., et al. (2002). Inflammation-dependent cerebral deposition of serum amyloid a protein in a mouse model of amyloidosis. Journal of Neuroscience, 22, 5900–5909.

    PubMed  CAS  Google Scholar 

  • Gyure, K. A., Durham, R., Stewart, W. F., et al. (2001). Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Archives of Pathology and Laboratory Medicine, 125, 489–492.

    PubMed  CAS  Google Scholar 

  • Haass, C., & Selkoe, D. J. (2007). Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid beta-peptide. Nature Reviews. Molecular Cell Biology, 8, 101–112.

    PubMed  CAS  Google Scholar 

  • Hampel, H., Broich, K., Hoessler, Y., et al. (2009). Biological markers for early detection and pharmacological treatment of Alzheimer’s disease. Dialogues in Clinical Neuroscience, 11, 141–157.

    PubMed  Google Scholar 

  • Hardy, J. A., & Higgins, G. A. (1992). Alzheimer’s disease: The amyloid cascade hypothesis. Science, 256, 184–185.

    PubMed  CAS  Google Scholar 

  • Hardy, J., & Orr, H. (2006). The genetics of neurodegenerative diseases. Journal of Neurochemistry, 97, 1690–1699.

    PubMed  CAS  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, 353–356.

    PubMed  CAS  Google Scholar 

  • Hauptmann, S., Scherping, I., Drose, S., et al. (2009). Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiology of Aging, 30, 1574–1586.

    PubMed  CAS  Google Scholar 

  • Herzig, M. C., Winkler, D. T., Burgermeister, P., et al. (2004). Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nature Neuroscience, 7, 954–960.

    PubMed  CAS  Google Scholar 

  • Hirai, K., Aliev, G., Nunomura, A., et al. (2001). Mitochondrial abnormalities in Alzheimer’s disease. Journal of Neuroscience, 21, 3017–3023.

    PubMed  CAS  Google Scholar 

  • Hirose, Y., Imai, Y., Nakajima, K., et al. (1994). Glial conditioned medium alters the expression of amyloid precursor protein in SH-SY5Y neuroblastoma cells. Biochemical and Biophysical Research Communications, 198, 504–509.

    PubMed  CAS  Google Scholar 

  • Holcomb, L., Gordon, M. N., McGowan, E., et al. (1998). Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nature Medicine, 4, 97–100.

    PubMed  CAS  Google Scholar 

  • Holmes, C., Boche, D., Wilkinson, D., et al. (2008). Long-term effects of Abeta42 immunisation in Alzheimer’s disease: Follow-up of a randomised, placebo-controlled phase I trial. Lancet, 372, 216–223.

    PubMed  CAS  Google Scholar 

  • Howlett, D. R., Bowler, K., Soden, P. E., et al. (2008). Abeta deposition and related pathology in an APP × PS1 transgenic mouse model of Alzheimer’s disease. Histology and Histopathology, 23, 67–76.

    PubMed  CAS  Google Scholar 

  • Howlett, D. R., Richardson, J. C., Austin, A., et al. (2004). Cognitive correlates of Abeta deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes. Brain Research, 1017, 130–136.

    PubMed  CAS  Google Scholar 

  • Hsia, A. Y., Masliah, E., McConlogue, L., et al. (1999). Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proceedings of the National Academy of Sciences of the United States of America, 96, 3228–3233.

    PubMed  CAS  Google Scholar 

  • Hsiao, K. K., Borchelt, D. R., Olson, K., et al. (1995). Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron, 15, 1203–1218.

    PubMed  CAS  Google Scholar 

  • Hsiao, K., Chapman, P., Nilsen, S., et al. (1996). Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science, 274, 99–102.

    PubMed  CAS  Google Scholar 

  • Hughes, R. N. (2004). The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neuroscience and Biobehavioral Reviews, 28, 497–505.

    PubMed  CAS  Google Scholar 

  • Hussain, I. (2010). APP transgenic mouse models and their use in drug discovery to evaluate amyloid-b lowering therapeutics. CNS & Neurological Disorders Drug Targets, 9, 395–402.

    CAS  Google Scholar 

  • Imbimbo, B. P. (2008). Therapeutic potential of gamma-secretase inhibitors and modulators. Current Topics in Medicinal Chemistry, 8, 54–61.

    PubMed  CAS  Google Scholar 

  • Irizarry, M. C., McNamara, M., Fedorchak, K., et al. (1997a). APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. Journal of Neuropathology and Experimental Neurology, 56, 965–973.

    PubMed  CAS  Google Scholar 

  • Irizarry, M. C., Soriano, F., McNamara, M., et al. (1997b). Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. Journal of Neuroscience, 17, 7053–7059.

    PubMed  CAS  Google Scholar 

  • Jack, C. R., Jr., Garwood, M., Wengenack, T. M., et al. (2004). In vivo visualization of Alzheimer’s amyloid plaques by magnetic resonance imaging in transgenic mice without a contrast agent. Magnetic Resonance in Medicine, 52, 1263–1271.

    PubMed  Google Scholar 

  • Jack, C. R., Jr., Marjanska, M., Wengenack, T. M., et al. (2007). Magnetic resonance imaging of Alzheimer’s pathology in the brains of living transgenic mice: A new tool in Alzheimer’s disease research. Neuroscientist, 13, 38–48.

    PubMed  CAS  Google Scholar 

  • Jack, C. R., Jr., Wengenack, T. M., Reyes, D. A., et al. (2005). In vivo magnetic resonance microimaging of individual amyloid plaques in Alzheimer’s transgenic mice. Journal of Neuroscience, 25, 10041–10048.

    PubMed  CAS  Google Scholar 

  • Jacobsen, J. S., Wu, C. C., Redwine, J. M., et al. (2006). Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 103, 5161–5166.

    PubMed  CAS  Google Scholar 

  • Janus, C., Pearson, J., McLaurin, J., et al. (2000). A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease. Nature, 408, 979–982.

    PubMed  CAS  Google Scholar 

  • Jarrett, J. T., Berger, E. P., & Lansbury, P. T., Jr. (1993). The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer’s disease. Biochemistry, 32, 4693–4697.

    PubMed  CAS  Google Scholar 

  • Jonas, E. (2006). BCL-xL regulates synaptic plasticity. Molecular Interventions, 6, 208–222.

    PubMed  CAS  Google Scholar 

  • Kalback, W., Watson, M. D., Kokjohn, T. A., et al. (2002). APP transgenic mice Tg2576 accumulate Abeta peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer’s disease senile plaques. Biochemistry, 41, 922–928.

    PubMed  CAS  Google Scholar 

  • Kamenetz, F., Tomita, T., Hsieh, H., et al. (2003). APP processing and synaptic function. Neuron, 37, 925–937.

    PubMed  CAS  Google Scholar 

  • Kelly, P. H., Bondolfi, L., Hunziker, D., et al. (2003). Progressive age-related impairment of cognitive behavior in APP23 transgenic mice. Neurobiology of Aging, 24, 365–378.

    PubMed  CAS  Google Scholar 

  • Khlistunova, I., Biernat, J., Wang, Y., et al. (2006). Inducible expression of Tau repeat domain in cell models of tauopathy: Aggregation is toxic to cells but can be reversed by inhibitor drugs. The Journal of Biological Chemistry, 281, 1205–1214.

    PubMed  CAS  Google Scholar 

  • Killiany, R. J., Gomez-Isla, T., Moss, M., et al. (2000). Use of structural magnetic resonance imaging to predict who will get Alzheimer’s disease. Annals of Neurology, 47, 430–439.

    PubMed  CAS  Google Scholar 

  • Kitazawa, M., Oddo, S., Yamasaki, T. R., et al. (2005). Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. Journal of Neuroscience, 25, 8843–8853.

    PubMed  CAS  Google Scholar 

  • Klein, W. L., Krafft, G. A., & Finch, C. E. (2001). Targeting small Abeta oligomers: The solution to an Alzheimer’s disease conundrum? Trends in Neurosciences, 24, 219–224.

    PubMed  CAS  Google Scholar 

  • Klunk, W. E., Bacskai, B. J., Mathis, C. A., et al. (2002). Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative. Journal of Neuropathology and Experimental Neurology, 61, 797–805.

    PubMed  CAS  Google Scholar 

  • Klunk, W. E., Lopresti, B. J., Ikonomovic, M. D., et al. (2005). Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer’s disease brain but not in transgenic mouse brain. Journal of Neuroscience, 25, 10598–10606.

    PubMed  CAS  Google Scholar 

  • Klunk, W. E., Wang, Y., Huang, G. F., et al. (2003). The binding of 2-(4’-methylaminophenyl)benzothiazole to postmortem brain homogenates is dominated by the amyloid component. Journal of Neuroscience, 23, 2086–2092.

    PubMed  CAS  Google Scholar 

  • Klyubin, I., Betts, V., Welzel, A. T., et al. (2008). Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: Prevention by systemic passive immunization. Journal of Neuroscience, 28, 4231–4237.

    PubMed  CAS  Google Scholar 

  • Knobloch, M., Konietzko, U., Krebs, D. C., et al. (2007). Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiology of Aging, 28, 1297–1306.

    PubMed  CAS  Google Scholar 

  • Kobayashi, D. T., & Chen, K. S. (2005). Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer’s disease. Genes, Brain, and Behavior, 4, 173–196.

    PubMed  CAS  Google Scholar 

  • Kotilinek, L. A., Bacskai, B., Westerman, M., et al. (2002). Reversible memory loss in a mouse transgenic model of Alzheimer’s disease. Journal of Neuroscience, 22, 6331–6335.

    PubMed  CAS  Google Scholar 

  • Kuo, Y. M., Beach, T. G., Sue, L. I., et al. (2001a). The evolution of A beta peptide burden in the APP23 transgenic mice: Implications for A beta deposition in Alzheimer disease. Molecular Medicine, 7, 609–618.

    PubMed  CAS  Google Scholar 

  • Kuo, Y. M., Crawford, F., Mullan, M., et al. (2000). Elevated A beta and apolipoprotein E in A betaPP transgenic mice and its relationship to amyloid accumulation in Alzheimer’s disease. Molecular Medicine, 6, 430–439.

    PubMed  CAS  Google Scholar 

  • Kuo, Y. M., Kokjohn, T. A., Beach, T. G., et al. (2001b). Comparative analysis of amyloid-beta chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer’s disease brains. The Journal of Biological Chemistry, 276, 12991–12998.

    PubMed  CAS  Google Scholar 

  • Kurt, M. A., Davies, D. C., Kidd, M., et al. (2001). Neurodegenerative changes associated with beta-amyloid deposition in the brains of mice carrying mutant amyloid precursor protein and mutant presenilin-1 transgenes. Experimental Neurology, 171, 59–71.

    PubMed  CAS  Google Scholar 

  • LaFerla, F. M., Green, K. N., & Oddo, S. (2007). Intracellular amyloid-beta in Alzheimer’s disease. Nature Reviews. Neuroscience, 8, 499–509.

    PubMed  CAS  Google Scholar 

  • Lalonde, R. (2002). The neurobiological basis of spontaneous alternation. Neuroscience and Biobehavioral Reviews, 26, 91–104.

    PubMed  CAS  Google Scholar 

  • Lamb, B. T., Sisodia, S. S., Lawler, A. M., et al. (1993). Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected]. Nature Genetics, 5, 22–30.

    PubMed  CAS  Google Scholar 

  • Langui, D., Girardot, N., El Hachimi, K. H., et al. (2004). Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice. American Journal of Pathology, 165, 1465–1477.

    PubMed  CAS  Google Scholar 

  • Larson, J., Lynch, G., Games, D., et al. (1999). Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice. Brain Research, 840, 23–35.

    PubMed  CAS  Google Scholar 

  • Lau, J. C., Lerch, J. P., Sled, J. G., et al. (2008). Longitudinal neuroanatomical changes determined by deformation-based morphometry in a mouse model of Alzheimer’s disease. Neuroimage, 42, 19–27.

    PubMed  Google Scholar 

  • Lee, M. K., Borchelt, D. R., Kim, G., et al. (1997). Hyperaccumulation of FAD-linked presenilin 1 variants in vivo. Nature Medicine, 3, 756–760.

    PubMed  CAS  Google Scholar 

  • Lee, S. P., Falangola, M. F., Nixon, R. A., et al. (2004). Visualization of beta-amyloid plaques in a transgenic mouse model of Alzheimer’s disease using MR microscopy without contrast reagents. Magnetic Resonance in Medicine, 52, 538–544.

    PubMed  Google Scholar 

  • Lee, J. W., Lee, Y. K., Yuk, D. Y., et al. (2008). Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. Journal of Neuroinflammation, 5, 37.

    PubMed  Google Scholar 

  • Lehman, E. J., Kulnane, L. S., Gao, Y., et al. (2003). Genetic background regulates beta-amyloid precursor protein processing and beta-amyloid deposition in the mouse. Human Molecular Genetics, 12, 2949–2956.

    PubMed  CAS  Google Scholar 

  • Lesne, S., Koh, M. T., Kotilinek, L., et al. (2006). A specific amyloid-beta protein assembly in the brain impairs memory. Nature, 440, 352–357.

    PubMed  CAS  Google Scholar 

  • Lovasic, L., Bauschke, H., & Janus, C. (2005). Working memory impairment in a transgenic amyloid precursor protein TgCRND8 mouse model of Alzheimer’s disease. Genes, Brain, and Behavior, 4, 197–208.

    PubMed  CAS  Google Scholar 

  • Lue, L. F., Kuo, Y. M., Roher, A. E., et al. (1999). Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. American Journal of Pathology, 155, 853–862.

    PubMed  CAS  Google Scholar 

  • Lustbader, J. W., Cirilli, M., Lin, C., et al. (2004). ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science, 304, 448–452.

    PubMed  CAS  Google Scholar 

  • Maeda, J., Ji, B., Irie, T., et al. (2007). Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer’s disease enabled by positron emission tomography. Journal of Neuroscience, 27, 10957–10968.

    PubMed  CAS  Google Scholar 

  • Maheswaran, S., Barjat, H., Rueckert, D., et al. (2009). Longitudinal regional brain volume changes quantified in normal aging and Alzheimer’s APP × PS1 mice using MRI. Brain Research, 1270, 19–32.

    PubMed  CAS  Google Scholar 

  • Manczak, M., Anekonda, T. S., Henson, E., et al. (2006). Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: Implications for free radical generation and oxidative damage in disease progression. Human Molecular Genetics, 15, 1437–1449.

    PubMed  CAS  Google Scholar 

  • Masliah, E., Sisk, A., Mallory, M., & Games, D. (2001). Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Journal of Neuropathology and Experimental Neurology, 60, 357–368.

    PubMed  CAS  Google Scholar 

  • Masters, C. L., Simms, G., Weinman, N. A., et al. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proceedings of the National Academy of Sciences of the United States of America, 82, 4245–4249.

    PubMed  CAS  Google Scholar 

  • Mattson, M. P. (2004). Pathways towards and away from Alzheimer’s disease. Nature, 430, 631–639.

    PubMed  CAS  Google Scholar 

  • Mattson, M. P., Gleichmann, M., & Cheng, A. (2008). Mitochondria in neuroplasticity and neurological disorders. Neuron, 60, 748–766.

    PubMed  CAS  Google Scholar 

  • Maurer, I., Zierz, S., & Moller, H. J. (2000). A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. Neurobiology of Aging, 21, 455–462.

    PubMed  CAS  Google Scholar 

  • McCool, M. F., Varty, G. B., Del Vecchio, R. A., et al. (2003). Increased auditory startle response and reduced prepulse inhibition of startle in transgenic mice expressing a double mutant form of amyloid precursor protein. Brain Research, 994, 99–106.

    PubMed  CAS  Google Scholar 

  • McGeer, P. L., Schulzer, M., & McGeer, E. G. (1996). Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: A review of 17 epidemiologic studies. Neurology, 47, 425–432.

    PubMed  CAS  Google Scholar 

  • McGowan, E., Sanders, S., Iwatsubo, T., et al. (1999). Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes. Neurobiology of Diseases, 6, 231–244.

    CAS  Google Scholar 

  • McLean, C. A., Cherny, R. A., Fraser, F. W., et al. (1999). Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Annals of Neurology, 46, 860–866.

    PubMed  CAS  Google Scholar 

  • Meyer-Luehmann, M., Spires-Jones, T. L., Prada, C., et al. (2008). Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature, 451, 720–724.

    PubMed  CAS  Google Scholar 

  • Moechars, D., Dewachter, I., Lorent, K., et al. (1999). Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. The Journal of Biological Chemistry, 274, 6483–6492.

    PubMed  CAS  Google Scholar 

  • Moran, P. M., Higgins, L. S., Cordell, B., et al. (1995). Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein. Proceedings of the National Academy of Sciences of the United States of America, 92, 5341–5345.

    PubMed  CAS  Google Scholar 

  • Morris, R. (1984). Developments of a water-maze procedure for studying spatial learning in the rat. Journal of Neuroscience Methods, 11, 47–60.

    PubMed  CAS  Google Scholar 

  • Morris, R. G., Garrud, P., Rawlins, J. N., & ET, A. L. (1982). Place navigation impaired in rats with hippocampal lesions. Nature, 297, 681–683.

    PubMed  CAS  Google Scholar 

  • Mosconi, L., De Santi, S., Li, J., et al. (2008). Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiology of Aging, 29, 676–692.

    PubMed  CAS  Google Scholar 

  • Mouri, A., Noda, Y., Hara, H., et al. (2007). Oral vaccination with a viral vector containing Abeta cDNA attenuates age-related Abeta accumulation and memory deficits without causing inflammation in a mouse Alzheimer model. The FASEB Journal, 21, 2135–2148.

    PubMed  CAS  Google Scholar 

  • Mucke, L. (2009). Neuroscience: Alzheimer’s disease. Nature, 461, 895–897.

    PubMed  CAS  Google Scholar 

  • Mucke, L., Masliah, E., Yu, G. Q., et al. (2000). High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation. Journal of Neuroscience, 20, 4050–4058.

    PubMed  CAS  Google Scholar 

  • Mullan, M., Crawford, F., Axelman, K., et al. (1992). A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nature Genetics, 1, 345–347.

    PubMed  CAS  Google Scholar 

  • Murrell, J., Farlow, M., Ghetti, B., et al. (1991). A mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science, 254, 97–99.

    PubMed  CAS  Google Scholar 

  • Nabeshi, H., Oikawa, S., Inoue, S., et al. (2006). Proteomic analysis for protein carbonyl as an indicator of oxidative damage in senescence-accelerated mice. Free Radical Research, 40, 1173–1181.

    PubMed  CAS  Google Scholar 

  • Naslund, J., Haroutunian, V., Mohs, R., et al. (2000). Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA, 283, 1571–1577.

    PubMed  CAS  Google Scholar 

  • Neff, F., Wei, X., Nolker, C., et al. (2008). Immunotherapy and naturally occurring autoantibodies in neurodegenerative disorders. Autoimmunity Reviews, 7, 501–507.

    PubMed  CAS  Google Scholar 

  • Nilsberth, C., Westlind-Danielsson, A., Eckman, C. B., et al. (2001). The ‘Arctic’ APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation. Nature Neuroscience, 4, 887–893.

    PubMed  CAS  Google Scholar 

  • Nordberg, A. (2008). Amyloid plaque imaging in vivo: Current achievement and future prospects. European Journal of Nuclear Medicine and Molecular Imaging 35(suppl 1), S46–S50.

    Google Scholar 

  • Oakley, H., Cole, S. L., Logan, S., et al. (2006). Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation. Journal of Neuroscience, 26, 10129–10140.

    PubMed  CAS  Google Scholar 

  • Oddo, S., Billings, L., Kesslak, J. P., et al. (2004). Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron, 43, 321–332.

    PubMed  CAS  Google Scholar 

  • Oddo, S., Caccamo, A., Shepherd, J. D., et al. (2003). Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron, 39, 409–421.

    PubMed  CAS  Google Scholar 

  • Oddo, S., Caccamo, A., Smith, I. F., et al. (2006a). A dynamic relationship between intracellular and extracellular pools of Abeta. American Journal of Pathology, 168, 184–194.

    PubMed  CAS  Google Scholar 

  • Oddo, S., Vasilevko, V., Caccamo, A., et al. (2006b). Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles. The Journal of Biological Chemistry, 281, 39413–39423.

    PubMed  CAS  Google Scholar 

  • Olton, D. S. (1987). The radial arm maze as a tool in behavioral pharmacology. Physiology & Behavior, 40, 793–797.

    CAS  Google Scholar 

  • Pallas, M., Camins, A., Smith, M. A., et al. (2008). From aging to Alzheimer’s disease: Unveiling “the switch” with the senescence-accelerated mouse model (SAMP8). Journal of Alzheimer’s Disease, 15, 615–624.

    PubMed  CAS  Google Scholar 

  • Palop, J. J., Jones, B., Kekonius, L., et al. (2003). Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer’s disease-related cognitive deficits. Proceedings of the National Academy of Sciences of the United States of America, 100, 9572–9577.

    PubMed  CAS  Google Scholar 

  • Pfeifer, M., Boncristiano, S., Bondolfi, L., et al. (2002). Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science, 298, 1379.

    PubMed  CAS  Google Scholar 

  • Phillips, R. G., & LeDoux, J. E. (1992). Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behavioral Neuroscience, 106, 274–285.

    PubMed  CAS  Google Scholar 

  • Pietropaolo, S., Feldon, J., & Yee, B. K. (2008). Age-dependent phenotypic characteristics of a triple transgenic mouse model of Alzheimer disease. Behavioral Neuroscience, 122, 733–747.

    PubMed  Google Scholar 

  • Poduslo, J. F., Wengenack, T. M., Curran, G. L., et al. (2002). Molecular targeting of Alzheimer’s amyloid plaques for contrast-enhanced magnetic resonance imaging. Neurobiology of Diseases, 11, 315–329.

    CAS  Google Scholar 

  • Pype, S., Moechars, D., Dillen, L., et al. (2003). Characterization of amyloid beta peptides from brain extracts of transgenic mice overexpressing the London mutant of human amyloid precursor protein. Journal of Neurochemistry, 84, 602–609.

    PubMed  CAS  Google Scholar 

  • Querfurth, H. W., & LaFerla, F. M. (2010). Alzheimer’s disease. New England Journal of Medicine, 362, 329–344.

    PubMed  CAS  Google Scholar 

  • Reaume, A. G., Howland, D. S., Trusko, S. P., et al. (1996). Enhanced amyloidogenic processing of the beta-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer’s disease mutations and a “humanized” Abeta sequence. The Journal of Biological Chemistry, 271, 23380–23388.

    PubMed  CAS  Google Scholar 

  • Redwine, J. M., Kosofsky, B., Jacobs, R. E., et al. (2003). Dentate gyrus volume is reduced before onset of plaque formation in PDAPP mice: A magnetic resonance microscopy and stereologic analysis. Proceedings of the National Academy of Sciences of the United States of America, 100, 1381–1386.

    PubMed  CAS  Google Scholar 

  • Rhein, V., Song, X., & Wiesner, A. (2009). Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proceedings of the National Academy of Sciences of the United States of America, 106(47), 20057–20062.

    PubMed  CAS  Google Scholar 

  • Rockenstein, E., Mallory, M., Mante, M., et al. (2001). Early formation of mature amyloid-beta protein deposits in a mutant APP transgenic model depends on levels of Abeta(1–42). Journal of Neuroscience Research, 66, 573–582.

    PubMed  CAS  Google Scholar 

  • Rogaev, E. I., Sherrington, R., Rogaeva, E. A., et al. (1995). Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature, 376, 775–778.

    PubMed  CAS  Google Scholar 

  • Roher, A. E., & Kokjohn, T. A. (2002). Of mice and men: The relevance of transgenic mice Abeta immunizations to Alzheimer’s disease. Journal of Alzheimer’s Disease, 4, 431–434.

    PubMed  CAS  Google Scholar 

  • Roher, A. E., Palmer, K. C., Capodilupo, J., et al. (1991). New biochemical insights to unravel the pathogenesis of Alzheimer’s lesions. Canadian Journal of Neurological Sciences, 18, 408–410.

    PubMed  CAS  Google Scholar 

  • Roher, A. E., Palmer, K. C., Yurewicz, E. C., et al. (1993). Morphological and biochemical analyses of amyloid plaque core proteins purified from Alzheimer disease brain tissue. Journal of Neurochemistry, 61, 1916–1926.

    PubMed  CAS  Google Scholar 

  • Roskam, S., Neff, F., Schwarting, R., et al. (2010). APP transgenic mice: The effect of active and passive immunotherapy in cognitive tasks. Neuroscience and Biobehavioral Reviews, 34, 487–499.

    PubMed  CAS  Google Scholar 

  • Rustay, N. R., Cronin, E. A., Curzon, P., et al. (2010). Mice expressing the Swedish APP mutation on a 129 genetic background demonstrate consistent behavioral deficits and pathological markers of Alzheimer’s disease. Brain Research, 1311, 136–147.

    PubMed  CAS  Google Scholar 

  • Santacruz, K., Lewis, J., Spires, T., et al. (2005). Tau suppression in a neurodegenerative mouse model improves memory function. Science, 309, 476–481.

    PubMed  CAS  Google Scholar 

  • Sastre, M., Dewachter, I., Landreth, G. E., et al. (2003). Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. Journal of Neuroscience, 23, 9796–9804.

    PubMed  CAS  Google Scholar 

  • Schenk, D., Barbour, R., Dunn, W., et al. (1999). Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature, 400, 173–177.

    PubMed  CAS  Google Scholar 

  • Schmitz, C., Rutten, B. P., Pielen, A., et al. (2004). Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer’s disease. American Journal of Pathology, 164, 1495–1502.

    PubMed  Google Scholar 

  • Scholtzova, H., Wadghiri, Y. Z., Douadi, M., et al. (2008). Memantine leads to behavioral improvement and amyloid reduction in Alzheimer’s-disease-model transgenic mice shown as by micromagnetic resonance imaging. Journal of Neuroscience Research, 86, 2784–2791.

    PubMed  CAS  Google Scholar 

  • Selkoe, D. J. (2008). Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behavioural Brain Research, 192, 106–113.

    PubMed  CAS  Google Scholar 

  • Shankar, G. M., Li, S., Mehta, T. H., et al. (2008). Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nature Medicine, 14, 837–842.

    PubMed  CAS  Google Scholar 

  • Sherrington, R., Rogaev, E. I., Liang, Y., et al. (1995). Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature, 375, 754–760.

    PubMed  CAS  Google Scholar 

  • Slangen, J. L., Earley, B., Jaffard, R., et al. (1990). Behavioral models of memory and amnesia. Pharmacopsychiatry, 23(Suppl 2), 81–83. (discussion 84).

    Google Scholar 

  • Snyder, E. M., Nong, Y., Almeida, C. G., et al. (2005). Regulation of NMDA receptor trafficking by amyloid-beta. Nature Neuroscience, 8, 1051–1058.

    PubMed  CAS  Google Scholar 

  • Spires, T. L., Meyer-Luehmann, M., Stern, E. A., et al. (2005). Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. Journal of Neuroscience, 25, 7278–7287.

    PubMed  CAS  Google Scholar 

  • Squire, L. R., Wixted, J. T., & Clark, R. E. (2007). Recognition memory and the medial temporal lobe: A new perspective. Nature Reviews. Neuroscience, 8, 872–883.

    PubMed  CAS  Google Scholar 

  • Steele, M., Stuchbury, G., & Munch, G. (2007). The molecular basis of the prevention of Alzheimer’s disease through healthy nutrition. Experimental Gerontology, 42, 28–36.

    PubMed  CAS  Google Scholar 

  • Sturchler-Pierrat, C., Abramowski, D., Duke, M., et al. (1997). Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proceedings of the National Academy of Sciences of the United States of America, 94, 13287–13292.

    PubMed  CAS  Google Scholar 

  • Takahashi, R. H., Almeida, C. G., Kearney, P. F., et al. (2004). Oligomerization of Alzheimer’s beta-amyloid within processes and synapses of cultured neurons and brain. Journal of Neuroscience, 24, 3592–3599.

    PubMed  CAS  Google Scholar 

  • Takahashi, R. H., Milner, T. A., Li, F., et al. (2002). Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. American Journal of Pathology, 161, 1869–1879.

    PubMed  CAS  Google Scholar 

  • Terry, R. D., Masliah, E., Salmon, D. P., 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, 572–580.

    PubMed  CAS  Google Scholar 

  • Townsend, M., Shankar, G. M., Mehta, T., et al. (2006). Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: A potent role for trimers. Journal of Physiology, 572, 477–492.

    PubMed  CAS  Google Scholar 

  • Trinchese, F., Fa, M., Liu, S., et al. (2008). Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. Journal of Clinical Investigation, 118, 2796–2807.

    PubMed  CAS  Google Scholar 

  • Van Broeck, B., Vanhoutte, G., Cuijt, I., et al. (2008a). Reduced brain volumes in mice expressing APP-Austrian mutation but not in mice expressing APP-Swedish-Austrian mutations. Neuroscience Letters, 447, 143–147.

    PubMed  Google Scholar 

  • Van Broeck, B., Vanhoutte, G., Pirici, D., et al. (2008b). Intraneuronal amyloid beta and reduced brain volume in a novel APP T714I mouse model for Alzheimer’s disease. Neurobiology of Aging, 29, 241–252.

    PubMed  Google Scholar 

  • Van Dam, D., D’Hooge, R., Staufenbiel, M., et al. (2003). Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. European Journal of Neuroscience, 17, 388–396.

    PubMed  Google Scholar 

  • Van Dam, D., & De Deyn, P. P. (2006). Drug discovery in dementia: The role of rodent models. Nature Reviews. Drug Discovery, 5, 956–970.

    PubMed  Google Scholar 

  • Vanhoutte, G., Dewachter, I., Borghgraef, P., et al. (2005). Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer’s disease. Magnetic Resonance in Medicine, 53, 607–613.

    PubMed  CAS  Google Scholar 

  • Walsh, D. M., Klyubin, I., Fadeeva, J. V., et al. (2002). Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 416, 535–539.

    PubMed  CAS  Google Scholar 

  • Walsh, D. M., & Selkoe, D. J. (2007). A beta oligomers - a decade of discovery. Journal of Neurochemistry, 101, 1172–1184.

    PubMed  CAS  Google Scholar 

  • Webster, S. D., Tenner, A. J., Poulos, T. L., et al. (1999). The mouse C1q A-chain sequence alters beta-amyloid-induced complement activation. Neurobiology of Aging, 20, 297–304.

    PubMed  CAS  Google Scholar 

  • Wegenast-Braun, B. M., Fulgencio Maisch, A., Eicke, D., et al. (2009). Independent effects of intra- and extracellular Abeta on learning-related gene expression. American Journal of Pathology, 175, 271–282.

    PubMed  CAS  Google Scholar 

  • Weiss, C., Venkatasubramanian, P. N., Aguado, A. S., et al. (2002). Impaired eyeblink conditioning and decreased hippocampal volume in PDAPP V717F mice. Neurobiology of Diseases, 11, 425–433.

    CAS  Google Scholar 

  • Wengenack, T.M., Jack, C.R., Jr., Garwood, M., et al. (2008). MR microimaging of amyloid plaques in Alzheimer’s disease transgenic mice. European Journal of Nuclear Medicine and Molecular Imaging, 35(Suppl 1), S82–S88.

    Google Scholar 

  • Westerman, M. A., Cooper-Blacketer, D., Mariash, A., et al. (2002). The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease. Journal of Neuroscience, 22, 1858–1867.

    PubMed  CAS  Google Scholar 

  • Wilcock, D. M., Rojiani, A., Rosenthal, A., et al. (2004). Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. Journal of Neuroscience, 24, 6144–6151.

    PubMed  CAS  Google Scholar 

  • Wirths, O., Multhaup, G., Czech, C., et al. (2001). Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Neuroscience Letters, 306, 116–120.

    PubMed  CAS  Google Scholar 

  • Wu, C. C., Chawla, F., Games, D., et al. (2004). Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: Digital morphometric analyses. Proceedings of the National Academy of Sciences of the United States of America, 101, 7141–7146.

    PubMed  CAS  Google Scholar 

  • Wyss-Coray, T., & Mucke, L. (2002). Inflammation in neurodegenerative disease–a double-edged sword. Neuron, 35, 419–432.

    PubMed  CAS  Google Scholar 

  • Yamaguchi, F., Richards, S. J., Beyreuther, K., et al. (1991). Transgenic mice for the amyloid precursor protein 695 isoform have impaired spatial memory. Neuroreport, 2, 781–784.

    PubMed  CAS  Google Scholar 

  • Yamin, G. (2009). NMDA receptor-dependent signaling pathways that underlie amyloid beta-protein disruption of LTP in the hippocampus. Journal of Neuroscience Research, 87, 1729–1736.

    PubMed  CAS  Google Scholar 

  • Yao, J., Irwin, R. W., Zhao, L., et al. (2009). Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 106, 14670–14675.

    PubMed  CAS  Google Scholar 

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Correspondence to Claudia Balducci.

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Balducci, C., Forloni, G. APP Transgenic Mice: Their Use and Limitations. Neuromol Med 13, 117–137 (2011). https://doi.org/10.1007/s12017-010-8141-7

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