Axonal accumulation of synaptic markers in APP transgenic Drosophila depends on the NPTY motif and is paralleled by defects in synaptic plasticity.
Alzheimer's disease (AD) is characterized by neurofibrillary tangles and extracellular plaques, which consist mainly of beta-amyloid derived from the beta-amyloid precursor protein (APP). An additional feature of AD is axonopathy, which might contribute to impairment of cognitive functions. Specifically, axonal transport defects have been reported in AD animal models, including mice and flies that overexpress APP and tau. Here we demonstrate that the APP-induced traffic jam of vesicles in peripheral nerves of Drosophila melanogaster larvae depends on the four residues NPTY motif in the APP intracellular domain. Furthermore, heterologous expression of Fe65 and JIP1b, scaffolding proteins interacting with the NPTY motif, also perturb axonal transport. Together, these data indicate that JIP1b or Fe65 may be involved in the APP-induced axonal transport defect. Moreover, we have characterized neurotransmission at the neuromuscular junction in transgenic larvae that express human APP. Consistent with the observation that these larvae do not show any obvious movement deficits, we found no changes in basal synaptic transmission. However, short-term synaptic plasticity was affected by overexpression of APP. Together, our results show that overexpression of APP induces partial stalling of axonal transport vesicles, paralleled by abnormalities in synaptic plasticity, which may provide a functional link to the deterioration of cognitive functions observed in AD.
Rusu
Patricia
P
Zentrum für Molekulare Biologie (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
Jansen
Anna
A
Soba
Peter
P
Kirsch
Joachim
J
Löwer
Alexander
A
Merdes
Gunter
G
Kuan
Yung-Hui
YH
Jung
Anita
A
Beyreuther
Konrad
K
Kjaerulff
Ole
O
Kins
Stefan
S
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D020816:Amino Acid Motifs / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism*; D004331:Drosophila melanogaster; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007814:Larva; D051379:Mice; D016296:Mutagenesis / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D050857:Synaptotagmins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; C490665:Mapk8ip protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D050857:Synaptotagmins; D049452:Green Fluorescent Proteins