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O4–02–01: Altered expression of APP gene family members in Drosophila cause defects in axonal transport and affect synaptic plasticity
Author(s) -
Kins Stefan,
Rusu Patricia,
Jansen Anna,
Soba Peter,
Merdes Gunther,
Kuan Yung-Hui,
Jung Anita,
Beyreuther Konrad,
Kjaerulff Ole
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.300
Subject(s) - microbiology and biotechnology , neuroscience , neurotransmission , axoplasmic transport , amyloid precursor protein , long term potentiation , synaptic plasticity , biology , synaptic vesicle , neuromuscular junction , intracellular , extracellular , synapse , neural facilitation , drosophila melanogaster , signal transducing adaptor protein , alzheimer's disease , excitatory postsynaptic potential , inhibitory postsynaptic potential , signal transduction , gene , biochemistry , medicine , vesicle , receptor , disease , membrane
Alzheimer’s disease (AD) is characterised by neurofibrillary tangles and extracellular plaques, which consist mainly of -amyloid derived from the -amyloid precursor protein (APP). Additional features of AD are axonal transport defects, which might contribute to impairment of cognitive functions. Axonal transport defects have also been reported in AD animal models, including mice and flies that overexpress APP and Tau. Here we demonstrate that APP-induced traffic jam of vesicles in peripheral nerves of Drosophila larvae depends on the NPTY motif in the APP intracellular domain. Furthermore, heterologous expression of JIP1b, an adaptor protein, which is able to bind to the NPTY-motif, also perturbs axonal transport indicating that JIP1b may be involved in the APP-induced axonal transport defect. Based on the assumption that APP-mediated transport defects might affect synaptic function, we have characterised neurotransmission at the neuromuscular junction in larvae that overexpress human APP, and in larvae missing APPL (the Drosophila homolog of APP), which display very similar axonal transport defects. We found that evoked responses were reduced and paired-pulse facilitation enhanced in APPL-deficient mutants but not in APP overexpressing flies. Moreover, post-tetanic potentiation was prolonged both by loss of APPL and overexpression of APP, possibly reflecting a defect in the homeostasis of intracellular Ca . Our results support the hypothesis that the APP gene family has essential functions in neurotransmission and that normal synaptic plasticity is affected by the APP/APPL-perturbed axonal transport. Thus, functional synaptic changes resulting from APP-related transport defects might affect cognitive function early in the course of AD.