Abstract
Development of therapeutics for Alzheimer’s disease (AD) requires appropriate cell culture models that reflect the errant biochemical pathways and animal models that reflect the pathological hallmarks of the disease as well as the clinical manifestations. In the past two decades AD research has benefited significantly from the use of genetically engineered cell lines expressing components of the amyloid-generating pathway, as well as from the study of transgenic mice that develop the pathological hallmarks of the disease, mainly neuritic plaques. The choice of certain cell types and the choice of mouse as the model organism have been mandated by the feasibility of introduction and expression of foreign genes into these model systems. We describe a universal and efficient gene-delivery system, using lentiviral vectors, that permits the development of relevant cell biological systems using neuronal cells, including primary neurons and animal models in mammalian species best suited for the study of AD. In addition, lentiviral gene delivery provides avenues for creation of novel models by direct and prolonged expression of genes in the brain in any vertebrate animal. TranzVector is a lentiviral vector optimized for efficiency and safety that delivers genes to cells in culture, in tissue explants, and in live animals regardless of the dividing or differentiated status of the cells. Genes can also be delivered efficiently to fertilized single-cell-stage embryos of a wide range of mammalian species, broadening the range of the model organism (from rats to nonhuman primates) for the study of disease mechanism as well as for development of therapeutics.
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Abbas-Terki T., Blanco-Bose W., Deglon N., Pralong W., and Aebischer P. (2002) Lentiviral-mediated RNA interference. Hum. Gene Ther. 13, 2197–2201.
Amalfitano A. (1999) In vivo neuronal targeting of genes, in Apoptosis in Neurobiology, Hannun, Y. A., and Boutsnay, R.-M., eds., CRC Press, New York, pp. 247–268.
Auerbach A. B., Norinsky R., Ho W., Losos K., Guo Q., Chatterjee S., and Joyner A. L. (2003) Strain differences in the efficiency of transgenic mouse production. Transgenic Res. 12, 59–69.
Baekelandt V., Claeys A., Eggermont K., Lauwers E., DeStrooper B., Nutting B., and Debyser Z. (2002) Characterization of lentiviral vector-mediated gene transfer in adult mouse brain. Hum. Gene Ther. 13, 841–853.
Blomer U., Naldini L., Kafri T., Trono D., Verma I. M., and Gage F. H. (1997) Highly efficient and sustained gene transfer in adult neurons with a lentivirus vector. J. Virol. 71, 6641–6649.
Burdon T. G. and Rall R. J. (1992) Fate of microinjected DNA in preimplantation mouse embryos. Mol. Reprod. Dev. 33, 436–442.
Cenci M. A., Whishaw I. Q., and Schallert T. (2002) Animal models for neurological deficits: how relevant is the rat? Nat. Rev. Neurosci. 3, 574–579.
Chishti M. A., Yang D.-S., Janus, C. Phinney A. L., Horne P., et al. (2001) Early-onset amyloid deposition and cognitive deficients in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J. Biol. Chem. 276, 21562–21570.
Citron M. (2002) Alzheimer’s disease: treatments in discovery and development. Nat. Neurosci. Suppl. 5, 1055–1057.
Craig A. M. (1998) Transfecting cultured neurons, in Culturing Nerve Cells, Banker, G., and Goslin, K., eds., MIT Press, Boston, MA, pp. 79–111.
de Almeida L. P., Ross C. A., Zala D., Aebisher P., and Deglon N. (2002) Lentiviral-mediated delivery of mutant huntingtin in striatum of rats induces a selective neuropathology modulated by polyglutamine repeat size, huntingtin expression levels, and protein length. J. Neurosci. 223, 473–3483.
Dodart J.-C., Mathis C., Bales K. R., and Paul S. M. (2002) Does my mouse have Alzheimer’s disease? Genes Brain Behav. 1, 142–155.
Games D., Adams D., Alessandrini R., Barbour R., Berthelette P., et al. (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527.
Gossen M, and Bujard H. (2002) Studying gene function in eukaryotes by conditional gene inactivation. Annu. Rev. Genet. 36, 153–173.
Greene L., Farinelli S. E., Cunningham M. E., and Park D. S. (1998) Culture and experimental use of PC12 rat pheochromocytoma cell line, in Culturing Nerve Cells, Banker, G., and Goslin, K., eds., MIT Press, Boston, MA, pp. 161–188.
Haugabook S. J., Yager D. M., Eckman T. E., Golde T. E., Younkin S. G., and Eckman C. B. (2001) High throughput screens for the identification of compounds that alter the accumulation of the Alzheimer’s amyloid β peptide (Aβ). J. Neurosci. Methods 108, 171–179.
Ishii K., Ii K., Hasegawa T., Shoji S., Doi A., and Mori H. (1997) Increased Abeta 42(43)-plaque deposition in early-onset familial Alzheimer’s disease brains with the deletion of exon 9 and the missense point mutation (H163R) in the PS-1 gene. Neurosci. Lett. 228, 17–20.
Kappes J. C. and Wu X. (2003) Safety considerations in vector development. in Lentiviral Vector Systems for Gene Transfer, Buchschacher, G. L., Jr., ed., Landes Bioscience, Georgetown, TX, pp. 147–158.
Kappes J. C., Wu X., and Wakefield J. K. (2003) Production of trans-lentiviral vector with predictable safety, in Virus Vectors for Gene Therapy: Methods and Protocols, Machida, C. A., ed, Humana Press, Totowa, NJ, pp. 449–465.
Kordower J. H., Emborg M. E., Bloch J., Ma Y. S., Chu Y, Leventhal L., et al. (2000) Neurodegeneration prevented by lentiviral delivery of GDNF in primate model of Parkinson’s disease. Science 290, 767–773.
Lever A. M. L. (1999) Lentiviral vectors, in Gene Therapy Technologies, Applications and Regulations, Meager, A., ed., Wiley, New York, pp. 61–86.
Lo Bianco C., Ridet J.-L., Schneider B. L., Deglon N., and Aebischer P. (2002) α-Synucleopathy and selective dopaminergic neuron loss in a rat model lentiviral-based model of Parkinson’s disease. Proc. Natl. Acad. Sci. U. S. A. 99, 10813–10818.
Lois C., Hong E. J., Pease S., Brown E. J., and Baltimore D. (2002) Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science 295, 868–872.
Naldini L. (1998) Lentiviruses as gene transfer agents for delivery to non-dividing cells. Curr. Opin. Biotechnol. 9, 457–463.
Naldini L., Blomer U., Gage F. H. Trono D., and Verma I. M. (1996) Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentivirus vector. Proc. Natl. Acad. Sci. U. S. A. 93, 11382–11388.
Oddo S., Caccamo A., Shepherd J. D., Murphy M.P., Golde T. E., Kayed, R., et al. (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39, 409–421.
Pfeifer A., Ikawa M., Dayn Y., and Verma I. M. (2002) Transgenesis by lentiviral vectors: lack of gene silencing in mammalian embryonic stem cells and preimplantation embryos. Proc. Natl. Acad. Sci. U. S. A. 99, 2140–2145.
Selkoe D. J. and Podlinsky M. B. (2002) Deciphering the genetic basis of Alzheimer’s disease. Annu. Rev. Genomics Hum. Genet. 3, 67–99.
Selkoe D. J. and Schenk D. (2003) Alzheimer’s disease: molecular understanding predicts amyloid-based therapeutics. Annu. Rev. Pharmacol. Toxicol. 43, 545–584.
Sherman M. P. and Greene W. C. (2002) Slipping through the door: HIV entry into the nucleus. Microbes Infection 4, 67–73.
Vagner S., Galy B., and Pyronnet S. (2001) Irresistible IRES. Attracting the translation machinery to internal ribosome entry sites. EMBO Rep. 2, 893–898.
Wells T. and Carter D. A. (2001) Genetic engineering of neuronal function in transgenic rodents: towards a comprehensive strategy? J. Neurosci. Methods 108, 111–130.
Whitelaw C. B., Springbett A. J., Webster J., and Clark J. (1993) Majority of the G0 transgenic mice are derived from mosaic embryos. Transgenic Res. 2, 29–32.
Wilkie T. M., Brinster R. L., and Palmiter R. D. (1986) Germline and somatic mosaicism in transgenic mice. Dev. Biol. 118, 9–18.
Wolfe M. S. (2002) Therapeutic strategies for Alzheimer’s disease. Nat. Rev. Drug Discovery 1, 859–866.
Wong C. W., Cai H., Borchelt D. R., and Price D. L. (2002) Genetically engineered mouse models of neurodegenerative diseases. Nat. Neurosci. 5, 633–639.
Wu X., Wakefield J. K., Liu H., Xiao H., Kralovics R., Prchal J. T., and Kappes J. C. (2000) Development of a novel trans-lentiviral vector that affords predictable safety. Mol. Ther. 2, 47–55.
Zennou V., Serguera C., Sarkis C., Colin P., Perret E., Mallet J., and Charneau P. (2001) The HIV-1 DNA flap stimulates HIV vector-mediated cell transduction in the brain. Nat. Biotechnol. 19, 446–450.
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Shaughnessy, L., Chamblin, B., McMahon, L. et al. Novel approaches to models of Alzheimer’s disease pathology for drug screening and development. J Mol Neurosci 24, 23–32 (2004). https://doi.org/10.1385/JMN:24:1:023
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DOI: https://doi.org/10.1385/JMN:24:1:023