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10 - Animal models of dementia

Published online by Cambridge University Press:  31 July 2009

By
Erik D. Roberson  and
Aimee W. Kao
Edited by
Bruce L. Miller  and
Bradley F. Boeve
Bruce L. Miller
Affiliation:
University of California, San Francisco
Bradley F. Boeve
Affiliation:
Mayo Foundation, Minnesota
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Summary

Recent decades have witnessed major advances in diagnosing neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), together with a wealth of new information about their clinical course and natural history. However, patients and physicians alike have been frustrated by the lack of available treatments. Solving this problem will require both a better understanding of the molecular mechanisms underlying these diseases and systems for screening the efficacy and safety of new therapeutics. There are several strategies for addressing these issues: studies of human patients themselves and human autopsy tissues, studies of animal models of disease, and more reductionist (cell culture or in vitro) models of disease. In this chapter, we will focus on animal models of neurodegenerative diseases, summarizing their relative advantages and disadvantages, highlighting some of the most important and widely studied models available, and reviewing a few important lessons that have emerged from animal model studies in recent years.

There is no question that studies of affected patients are the “gold standard” for understanding a human disease. As such, animal model studies depend fully on such human research. For example, human genetic studies has identified the mutations that have been used to generate most animal models of disease. Obviously, though, there are advantages to using animal models, and it is useful to consider them explicitly, as they help to clarify both the power and the limitations of animal models.

  1. Ability to study early stages of the disease. Therapies are most likely to be effective when delivered early in the disease, before irreversible cell death or other changes occur, making it critical to understand the pathophysiology underlying initial stages.

  2. […]

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The Behavioral Neurology of Dementia , pp. 131 - 141
Publisher: Cambridge University Press
Print publication year: 2009

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References

Adams, M. D., Celniker, S. E., Holt, R. A.et al. 2000. The genome sequence of Drosophila melanogaster. Science 287, 2185–2195.CrossRefGoogle ScholarPubMed
Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R., Finkbeiner, S. 2004. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805–810.CrossRefGoogle ScholarPubMed
Baker, M., Mackenzie, I. R., Pickering-Brown, S. M.et al. 2006. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919.CrossRefGoogle ScholarPubMed
Baki, L., Shioi, J., Wen, P.et al. 2004. PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J. 23, 2586–2596.CrossRefGoogle ScholarPubMed
Bargmann, C. I. 1998. Neurobiology of the Caenorhabditis elegans genome. Science 282, 2028–2033.CrossRefGoogle ScholarPubMed
Bertram, L., McQueen, M. B., Mullin, K., Blacker, D., Tanzi, R. E. 2007. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat. Genet. 39, 17–23.CrossRefGoogle ScholarPubMed
Borchelt, D. R., Thinakaran, G., Eckman, C. B.et al. 1996. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1–42/1–40 ratio in vitro and in vivo. Neuron 17, 1005–1013.CrossRefGoogle ScholarPubMed
Borchelt, D. R., Ratovitski, T., 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.CrossRefGoogle ScholarPubMed
Brenner, S. 1973. The genetics of behaviour. Br. Med. Bull. 29, 269–271.CrossRefGoogle ScholarPubMed
Buttini, M., Orth, M., Bellosta, S.et al. 1999. Expression of human apolipoprotein E3 or E4 in the brains of Apoe–/– mice: isoform-specific effects on neurodegeneration. J. Neurosci. 19, 4867–4880.CrossRefGoogle ScholarPubMed
Buttini, M., Yu, G.-Q., Shockley, K.et al. 2002. Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid β peptides but not on plaque formation. J. Neurosci. 22, 10539–10548.CrossRefGoogle Scholar
Chin, J., Palop, J. J., Yu, G.-Q.et al. 2004. Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. J. Neurosci. 24, 4692–4697.CrossRefGoogle 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. J. Biol. Chem. 276, 21562–21570.CrossRefGoogle ScholarPubMed
Clark, L. N., Poorkaj, P., Wszolek, Z.et al. 1998. Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc. Natl. Acad. Sci. USA 95, 13103–13107.CrossRefGoogle ScholarPubMed
Cleary, J. P., Walsh, D. M., Hofmeister, J. J.et al. 2005. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat. Neurosci. 8, 79–84.CrossRefGoogle ScholarPubMed
Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W., Dillin, A. 2006. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604–1610.CrossRefGoogle ScholarPubMed
Crawley, J. N. 2000. What's Wrong with my Mouse?: Behavioral Phenotyping of Transgenic and Knockout Mice. New York: Wiley-Liss.Google Scholar
Cruts, M., Rademakers, R. 2008. Alzheimer Disease and Frontotemporal Dementia Mutation Database. http://www.molgen.ua.ac.be/ADMutations/default.cfm. (accessed October 2008).
Cruts, M., Gijselinck, I., Zee, J.et al. 2006. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–924.CrossRefGoogle ScholarPubMed
Dabir, D. V., Robinson, M. B., Swanson, E.et al. 2006. Impaired glutamate transport in a mouse model of tau pathology in astrocytes. J. Neurosci. 26, 644–654.CrossRefGoogle Scholar
Daigle, I., Li, C. 1993. apl-1, a Caenorhabditis elegans gene encoding a protein related to the human β-amyloid protein precursor. Proc. Natl. Acad. Sci. USA 90, 12045–12049.CrossRefGoogle ScholarPubMed
Duff, K., Eckman, C., Zehr, C.et al. 1996. Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 383, 710–713.CrossRefGoogle ScholarPubMed
Farrer, L. A., Cupples, L. A., Haines, J. L.et al. 1997. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. JAMA 278, 1349–1356.CrossRefGoogle ScholarPubMed
Feany, M. B., Bender, W. W. 2000. A Drosophila model of Parkinson's disease. Nature 404, 394–398.CrossRefGoogle ScholarPubMed
Fire, A., Xu, S., Montgomery, M. K.et al. 1998. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811.CrossRefGoogle ScholarPubMed
Forman, M. S., Lal, D., Zhang, B.et al. 2005. Transgenic mouse model of tau pathology in astrocytes leading to nervous system degeneration. J. Neurosci. 25, 3539–3550.CrossRefGoogle ScholarPubMed
Games, D., Adams, D., Alessandrini, R.et al. 1995. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527.CrossRefGoogle ScholarPubMed
Gunawardena, S., Goldstein, L. S. B. 2001. Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32, 389–401.CrossRefGoogle ScholarPubMed
Harris, F., Brecht, W. J., Xu, Q.et al. 2003. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc. Natl. Acad. Sci. USA 100, 10966–10971.CrossRefGoogle ScholarPubMed
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. Nat. Med. 4, 97–100.CrossRefGoogle ScholarPubMed
Holtzman, D. M., Bales, K. R., Tenkova, T.et al. 2000. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 97, 2892–2897.CrossRefGoogle Scholar
Hsiao, K., Chapman, P., Nilsen, S.et al. 1996. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102.CrossRefGoogle ScholarPubMed
Huang, Y., Liu, X. Q., Wyss-Coray, T.et al. 2001. Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc. Natl. Acad. Sci. USA 98, 8838–8843.CrossRefGoogle ScholarPubMed
Hutton, M., Lendon, C. L., Rizzu, P.et al. 1998. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705.CrossRefGoogle ScholarPubMed
Irizarry, M. C., McNamara, M., Fedorchak, K., Hsiao, K., Hyman, B. T. 1997a. APPSw transgenic mice develop age-related Aβ deposits and neuropil abnormalities, but no neuronal loss in CA1. J. Neuropathol. Exp. Neurol. 56, 965–973.CrossRefGoogle Scholar
Irizarry, M. C., Soriano, F., McNamara, M.et al. 1997b. Aβ deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J. Neurosci. 17, 7053–7059.CrossRefGoogle Scholar
Jackson, G. R., Wiedau-Pazos, M., Sang, T. K.et al. 2002. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34, 509–519.CrossRefGoogle ScholarPubMed
Janus, C., D'Amelio, S., Amitay, O.et al. 2000. Spatial learning in transgenic mice expressing human presenilin 1 (PS1) transgenes. Neurobiol. Aging 21, 541–549.CrossRefGoogle Scholar
Karsten, S. L., Sang, T. K., Gehman, L. T.et al. 2006. A genomic screen for modifiers of tauopathy identifies puromycin-sensitive aminopeptidase as an inhibitor of tau-induced neurodegeneration. Neuron 51, 549–560.CrossRefGoogle ScholarPubMed
Kasri, N. N., Kocks, S. L., Verbert, L.et al. 2006. Up-regulation of inositol 1,4,5-trisphosphate receptor type 1 is responsible for a decreased endoplasmic-reticulum Ca2+ content in presenilin double knock-out cells. Cell Calcium 40, 41–51.CrossRefGoogle ScholarPubMed
Kenyon, C., Chang, J., Gensch, E., Rudner, A., Tabtiang, R. 1993. A C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464.CrossRefGoogle Scholar
Kobayashi, D. T., Chen, K. S. 2005. Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer's disease. Genes Brain Behav. 4, 173–196.CrossRefGoogle ScholarPubMed
Kraemer, B. C., Zhang, B., Leverenz, J. B.et al. 2003. Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc. Natl. Acad. Sci. USA 100, 9980–9985.CrossRefGoogle Scholar
LaFerla, F. M. 2002. Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease. Nat. Rev. Neurosci. 3, 862–872.CrossRefGoogle ScholarPubMed
Lanz, T. A., Carter, D. B., Merchant, K. M. 2003. Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol. Dis. 13, 246–253.CrossRefGoogle ScholarPubMed
Leissring, M. A., Akbari, Y., Fanger, C. M.et al. 2000. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J. Cell Biol. 149, 793–798.CrossRefGoogle ScholarPubMed
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R.et al. 2006. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357.CrossRefGoogle ScholarPubMed
Lewis, J., McGowan, E., Rockwood, J.et al. 2000. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402–405.CrossRefGoogle ScholarPubMed
Lewis, J., Dickson, D. W., Lin, W. L.et al. 2001. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491.CrossRefGoogle ScholarPubMed
Leyssen, M., Ayaz, D., Hébert, S. S.et al. 2005. Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain. EMBO J. 24, 2944–2955.CrossRefGoogle ScholarPubMed
Link, C. D., Taft, A., Kapulkin, V.et al. 2003. Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model. Neurobiol. Aging 24, 397–413.CrossRefGoogle Scholar
Luo, L., Tully, T., White, K. 1992. Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene. Neuron 9, 595–605.CrossRefGoogle ScholarPubMed
Marx, J. 2002. Nobel Prize in Physiology or Medicine. Tiny worm takes a star turn. Science 298, 526.CrossRefGoogle ScholarPubMed
Masliah, E., Rockenstein, E., Veinbergs, I.et al. 2001. β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc. Natl. Acad. Sci. USA 98, 12245–12250.CrossRefGoogle Scholar
McGowan, E., Eriksen, J., Hutton, M. 2006. A decade of modeling Alzheimer's disease in transgenic mice. Trends Genet. 22, 281–289.CrossRefGoogle ScholarPubMed
Moolman, D. L., Vitolo, O. V., Vonsattel, J. P., Shelanski, M. L. 2004. Dendrite and dendritic spine alterations in Alzheimer models. J. Neurocytol. 33, 377–387.CrossRefGoogle ScholarPubMed
Mucke, L., Masliah, E., Yu, G.-Q.et al. 2000. High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058.CrossRefGoogle Scholar
Neumann, M., Sampathu, D. M., Kwong, L. K.et al. 2006. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133.CrossRefGoogle ScholarPubMed
Nicoll, J. A., Wilkinson, D., Holmes, C.et al. 2003. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat. Med. 9, 448–452.CrossRefGoogle ScholarPubMed
Nicoll, J. A., Barton, E., Boche, D.et al. 2006. Aβ species removal after Aβ42 immunization. J. Neuropathol. Exp. Neurol. 65, 1040–1048.CrossRefGoogle ScholarPubMed
Nishimura, I., Yang, Y., Lu, B. 2004. PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila. Cell 116, 671–682.CrossRefGoogle Scholar
Oddo, S., Caccamo, A., Shepherd, J. D.et al. 2003. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39, 409–421.CrossRefGoogle ScholarPubMed
Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H., LaFerla, F. M. 2004. Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321–332.CrossRefGoogle 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. Proc. Natl. Acad. Sci. USA 100, 9572–9577.CrossRefGoogle ScholarPubMed
Palop, J. J., Chin, J., Mucke, L. 2006. A network dysfunction perspective on neurodegenerative diseases. Nature 443, 768–773.CrossRefGoogle ScholarPubMed
Payami, H., Zareparsi, S., Montee, K. R.et al. 1996. Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am. J. Hum. Genet. 58, 803–811.Google ScholarPubMed
Perl, D. P., Olanow, C. W., Calne, D. 1998. Alzheimer's disease and Parkinson's disease: distinct entities or extremes of a spectrum of neurodegeneration?Ann. Neurol. 44, S19–31.CrossRefGoogle ScholarPubMed
Poorkaj, P., Bird, T. D., Wijsman, E.et al. 1998. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825.CrossRefGoogle ScholarPubMed
Raber, J. 2004. Androgens, apoE, and Alzheimer's disease. Sci. Aging Knowl. Environ. 11, re2.Google Scholar
Raber, J., Wong, D., Buttini, M.et al. 1998. Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proc. Natl. Acad. Sci. USA 95, 10914–10919.CrossRefGoogle ScholarPubMed
Raber, J., Wong, D., Yu, G.-Q.et al. 2000. Alzheimer's disease: apolipoprotein E and cognitive performance. Nature 404, 352–354.CrossRefGoogle ScholarPubMed
Raber, J., LeFevour, A., Buttini, M., Mucke, L. 2002. Androgens protect against apolipoprotein E4-induced cognitive deficits. J. Neurosci. 22, 5204–5209.CrossRefGoogle ScholarPubMed
Raber, J., Huang, Y., Ashford, J. W. 2004. ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol. Aging 25, 641–650.CrossRefGoogle ScholarPubMed
Roberson, E. D. 2006. Frontotemporal dementia. Curr. Neurol. Neurosci. Rep. 6, 481–489.CrossRefGoogle ScholarPubMed
Roberson, E. D., Mucke, L. 2006. 100 years and counting: prospects for defeating Alzheimer's disease. Science 314, 781–784.CrossRefGoogle ScholarPubMed
Roberson, E. D., Scearce-Levie, K., Palop, J. J.et al. 2007. Reducing endogenous tau ameliorates Aβ-induced deficits in an Alzheimer's disease mouse model. Science 316, 750–754.CrossRefGoogle Scholar
Rosen, D. R., Martin-Morris, L., Luo, L. Q., White, K. 1989. A Drosophila gene encoding a protein resembling the human β-amyloid protein precursor. Proc. Natl. Acad. Sci. USA 86, 2478–2482.CrossRefGoogle ScholarPubMed
Rubin, G. M., Yandell, M. D., Wortman, J. R.et al. 2000. Comparative genomics of the eukaryotes. Science 287, 2204–2215.CrossRefGoogle ScholarPubMed
SantaCruz, K., Lewis, J., Spires, T.et al. 2005. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481.CrossRefGoogle Scholar
Saunders, A. M., Strittmatter, W. J., Schmechel, D.et al. 1993. Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43, 1467–1472.CrossRefGoogle Scholar
Saura, C. A., Choi, S. Y., Beglopoulos, V.et al. 2004. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron 42, 23–36.CrossRefGoogle ScholarPubMed
Schenk, D., Barbour, R., Dunn, W.et al. 1999. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177.CrossRefGoogle ScholarPubMed
Scheuner, D., Eckman, C., Jensen, M.et al. 1996. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat. Med. 2, 864–870.CrossRefGoogle ScholarPubMed
Selkoe, D. J. 2002. Alzheimer's disease is a synaptic failure. Science 298, 789–791.CrossRefGoogle ScholarPubMed
Shen, J., Kelleher, R. J., III 2007. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc. Natl. Acad. Sci. USA 104, 403–409.CrossRefGoogle ScholarPubMed
Skibinski, G., Parkinson, N. J., Brown, J. M.et al. 2005. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806–808.CrossRefGoogle ScholarPubMed
Spillantini, M. G., Murrell, J. R., Goedert, M.et al. 1998. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95, 7737–7741.CrossRefGoogle ScholarPubMed
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. J. Neurosci. 25, 7278–7287.CrossRefGoogle ScholarPubMed
Sturchler-Pierrat, C., Abramowski, D., Duke, M.et al. 1997. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl. Acad. Sci. USA 94, 13287–13292.CrossRefGoogle ScholarPubMed
Takeuchi, A., Irizarry, M. C., Duff, K.et al. 2000. Age-related amyloid β deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss. Am. J. Pathol. 157, 331–339.CrossRefGoogle Scholar
Tecott, L. H. 2003. The genes and brains of mice and men. Am. J. Psychiatry 160, 646–656.CrossRefGoogle ScholarPubMed
,The C. elegans Sequencing Consortium. 1998. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science282, 2012–2018.
Torroja, L., Packard, M., Gorczyca, M., White, K., Budnik, V. 1999a. The Drosophila β-amyloid precursor protein homolog promotes synapse differentiation at the neuromuscular junction. J. Neurosci. 19, 7793–7803.CrossRefGoogle ScholarPubMed
Torroja, L., Chu, H., Kotovsky, I., White, K. 1999b. Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport. Curr. Biol. 9, 489–492.CrossRefGoogle Scholar
Trommer, B. L., Shah, C., Yun, S. H.et al. 2004. ApoE isoform affects LTP in human targeted replacement mice. Neuroreport 15, 2655–2658.CrossRefGoogle ScholarPubMed
Tu, H., Nelson, O., Bezprozvanny, A.et al. 2006. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. Cell 126, 981–993.CrossRefGoogle ScholarPubMed
Walsh, D. M., Klyubin, I., Fadeeva, J. V.et al. 2002. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539.CrossRefGoogle ScholarPubMed
Watts, G. D., Wymer, J., Kovach, M. J.et al. 2004. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36, 377–381.CrossRefGoogle ScholarPubMed
Westerman, M. A., Cooper-Blacketer, D., Mariash, A.et al. 2002. The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer's disease. J. Neurosci. 22, 1858–1867.CrossRefGoogle ScholarPubMed
Wittmann, C. W., Wszolek, M. F., Shulman, J. M.et al. 2001. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293, 711–714.CrossRefGoogle ScholarPubMed
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. Proc. Natl. Acad. Sci. USA 101, 7141–7146.CrossRefGoogle ScholarPubMed
Xu, Q., Bernardo, A., Walker, D.et al. 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. J. Neurosci. 26, 4985–4994.CrossRefGoogle ScholarPubMed
Yoshihara, M., Ensminger, A. W., Littleton, J. T. 2001. Neurobiology and the Drosophila genome. Funct. Integr. Genomics 1, 235–240.CrossRefGoogle ScholarPubMed
Yoshiyama, Y., Higuchi, M., Zhang, B.et al. 2007. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351.CrossRefGoogle Scholar

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