Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease whose main pathomorphological sign is synapse degeneration in the cortex and hippocampus. Abnormal synaptogenesis precedes amyloidosis and neurodegeneration and correlates with memory impairment during the early clinical phase. Mutations in the amyloid precursor protein (APP) gene cause familial AD and enhance the secretion of amyloid-β protein (Aβ). However, it remains unclear in what way APP and Aβ- are involved in synaptic disorder in the absence of visible amyloid structures. In this study, the role of the human APP gene in synaptogenesis in transgenic lines of Drosophila melanogaster whose nerve cells express the human APP695 isoform, truncated APPs, and the presynaptic marker synaptotagmin containing the green fluorescent protein (GFP) sequence. The expression of APP and its truncated forms caused a decrease in the synaptotagmin content of antennal lobes (ALs) and mushroom bodies (MBs) of the D. melanogaster brain, as well as neurodegeneration that progressed with age. The results suggest that abnormal synaptogenesis and neurodegeneration occur in the Drosophila brain in the absence of β-. It is assumed that impaired cellular functions of APP and secretion of β- independently contribute to the pathogenesis of AD.
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Davis, K.L. and Samuels, S.C., in Pharmacological Management of Neurological and Psychiatric Disorders, New York: McGraw-Hill, 1998, pp. 267–316.
George-Hyslop, P.H., Genetic Factors in the Genesis of Alzheimer’s Disease, Ann. N.Y. Acad. Sci., 2000, vol. 924, pp. 1–7.
Terry, R.D., The Pathogenesis of Alzheimer’s Disease: What Causes Dementia?, in Neurophilosophy and Alzheimer’s Disease, Christen, Y., et al., Eds., Berlin: Springer, 1992, pp. 123–130.
Terry, R.D., Where in the Brain Does Alzheimer’s Disease Begin?, Ann. Neurol., 2000, vol. 47, p. 421.
Masliah, E., Mallory, M., Hansen, L., et al., Synaptic and Neuritic Alterations during the Progression of Alzheimer’s Disease, Neurosci. Lett., 1994, vol. 174, pp. 67–72.
Hardy, J.A. and Higgins, G.A., Alzheimer’s Disease: The Amyloid Cascade Hypothesis, Science, 1992, vol. 256, pp. 184–185.
Hardy, J. and Selkoe, D.J., The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics: An Updated Summary of the Amyloid Hypothesis, Science, 2002, vol. 297, pp. 353–356.
Walsh, D.M. and Selkoe, D.J., Deciphering the Molecular Basis of Memory Failure in Alzheimer’s Disease, Neuron, 2004, vol. 44, pp. 181–193.
Oddo, S., Caccamo, A., Shepherd, J.D., et al., Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles: Intracellular Abeta and Synaptic Dysfunction, Neuron, 2003, vol. 39, pp. 409–21.
Stenh, C., Nilsbert, C., Hammarback, J., et al., The Arctic Mutation Interferes with Processing of the Amyloid Precursor Protein, Neuroreport, 2002, vol. 13, pp. 1857–1860.
Bentahir, M., Nyabi, O., Verhamme, J., et al., Presenilin Clinical Mutations Can Affect γ Secretase Activity by Different Mechanisms, J. Neurochem., 2006, vol. 96, pp. 732–742.
Kumar-Singh, S., Theuns, J., Van Broeck, B., et al., Mean Age-of-Onset of Familial Alzheimer Disease Caused by Presenilin Mutations Correlates with Both Increased Aβ-42 and Decreased Aβ-40, Hum. Mutation, 2006, vol. 27, pp. 686–695.
Littleton, J.T., Bellen, H.J., and Perin, M.S., Expression of Synaptotagmin in Drosophila Reveals Transport and Localization of Synaptic Vesicles to the Synapse, Development, 1993, vol. 118, pp. 1077–108814.
Masliah, E., Mallory, M., Alford, M., et al., Altered Expression of Synaptic Proteins Occurs Early during Progression of Alzheimer’s Disease, Neurology, 2001, vol. 127–129.
Yao, P.J., Bushlin, I., and Furukawa, K., Preserved Synaptic Vesicle Recycling in Hippocampal Neurons in a Mouse Alzheimer’s Disease Model, Biochem. Biophys. Res. Commun., 2005, vol. 330, pp. 34–38.
Kiseli, D., Prakticheskaya mikrotekhnika i gistokhimiya (Practical Microtechnique and Histochemistry), Budapest: Akad. Nauk Vengrii, 1962.
De Strooper, B. and Annaert, W., Proteolytic Processing and Cell Biological Functions of the Amyloid Precursor Protein, J. Cell Sci., 2000, vol. 113, pp. 1857–1870.
Hardy, J., Amyloid, the Presenilins and Alzheimer’s Disease, Trends Neurosci., 1997, vol. 20, pp. 154–159.
Mullan, M., Crawford, F., Axelman, K., et al., A Pathogenic Mutation for Probable Alzheimer’s Disease in the APP Gene at the N-Terminus of β Amyloid, Nat. Genet., 1992, vol. 1, pp. 345–347.
Moechars, D. and Dewachter, I., Lorent, K., et al., Early Phenotypic Changes in Transgenic Mice That Overexpress Different Mutants of Amyloid Precursor Protein in Brain, J. Biol. Chem., 1999, vol. 274, pp. 6483–6492.
Krezowski, J., Knudson, D., Ebeling, C., et al., Identification of Loci Determining Susceptibility to the Lethal Effects of Amyloid Precursor Protein Transgene Overexpression, Hum. Mol. Gen., 2004, vol. 13, pp. 1989–1997.
Ting, J.T., Kelley, B.G., Lambert, T.J., et al., Amyloid Precursor Protein Overexpression Depresses Excitatory Transmission through Both Presynaptic and Postsynaptic Mechanisms, Proc. Natl. Acad. Sci. USA, 2007, vol. 104, pp. 353–358.
Saura, C.A., Choi, S.-Y., Beglopoulos, V., et al., Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration, Neuron, 2004, vol. 42, pp. 23–36.
Sarantseva, S.V. and Shvartsman, A.L., Alzheimer’s Disease: Amyloidosis or Synaptic Dysfunction? Lessons from Drosophila melanogaster Model, Ekol. Genet., 2005, vol. 3, pp. 19–25.
Dyrks, T., Dyrks, E., Masters, C., and Beyreuther, K., Membrane Inserted APP Fragments Containing the flA4 Sequence of Alzheimer’s Disease Do not Aggregate, FEBS Lett., 1992, vol. 309, pp. 20–24.
Tienari, P.J., De Strooper, B., Ikonen, E., et al., The Beta-Amyloid Domain Is Essential for Axonal Sorting of Amyloid Precursor Protein, EMBO J., 1996, vol. 15, pp. 5218–5229.
Adolfsen, B., Saraswati, S., Yoshihara, M., and Littleton, J.T., Synaptotagmins Are Trafficked to Distinct Subcellular Domains Including the Postsynaptic Compartment, J. Cell Biol., 2004, vol. 166, pp. 249–260.
Zhang, Y.Q., Rodesch, C.K., and Broadie, K., Living Synaptic Vesicle Marker: Synaptotagmin-GFP, Genesis, 2002, vol. 34, pp. 142–145.
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Original Russian Text © S.V. Sarantseva, O.I. Bolshakova, S.I. Timoshenko, D.I. Rodin, M. Vitek, A.L. Schwarzman, 2009, published in Genetika, 2009, Vol. 45, No. 1, pp. 119–126.
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Sarantseva, S.V., Bolshakova, O.I., Timoshenko, S.I. et al. Studying the pathogenesis of Alzheimer’s disease in a Drosophila melanogaster model: Human APP overexpression in the brain of transgenic flies leads to deficit of the synaptic protein synaptotagmin. Russ J Genet 45, 105–112 (2009). https://doi.org/10.1134/S1022795409010153
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DOI: https://doi.org/10.1134/S1022795409010153