Abstract
APP (amyloid precursor protein), the causative molecule of Alzheimer's disease, is synthesized in neuronal cell bodies and subsequently transported to synapses. We previously showed that the yata gene is required for the synaptic transport of the APP orthologue in Drosophila melanogaster. In this study, we examined the effect of a reduction in yata expression in the Drosophila Alzheimer's disease model, in which expression of human mutant APP was induced. The synaptic localization of APP and other synaptic proteins was differentially inhibited by yata knockdown and null mutation. Expression of APP resulted in abnormal synaptic morphology and the premature death of animals. These phenotypes were partially but significantly rescued by yata knockdown, whereas yata knockdown itself caused no abnormality. Moreover, we observed that synaptic transmission accuracy was impaired in our model, and this phenotype was improved by yata knockdown. Thus, our data suggested that the phenotypes caused by APP can be partially prevented by inhibition of the synaptic localization of a subset of synaptic proteins including APP.
Highlights
APP is one of the causative genes of the familial type of Alzheimer’s disease
We examined the localization of Fasciclin II, which is a cell adhesion molecule localized to both the pre- and postsynaptic membrane [34, 48], Synaptotagmin, which is a synaptic vesicle membrane protein that plays a role in the exocytosis of synaptic vesicles [49, 50], and Cysteine string protein, which is a protein that is associated with synaptic vesicles and is involved in regulated neurotransmitter release [41, 51]
Our data showed that synaptic localization of APP was impaired whereas localization of Fasciclin II was not significantly affected by yata knockdown
Summary
APP (amyloid precursor protein) is one of the causative genes of the familial type of Alzheimer’s disease. Mammalian APP can rescue the mutant phenotype of null mutants of the Drosophila Appl gene affecting the fast phototaxis, suggesting that the physiological function of APP is conserved between Drosophila and mammals [30]. In the null mutant of yata, aberrant accumulation of APPL is observed in neuronal cell bodies, whereas transport of other synaptic molecules, such as synaptotagmin, is not affected. This phenotype is suggested to be caused by impaired vesicular protein trafficking because aberrant accumulation of the COPII coat protein of secretory vesicles traveling from the endoplasmic reticulum to the Golgi is observed in yata mutants. Our data showed that yata mutation resulted in the reduction of the synaptic localization of a subset of proteins including APP, which caused significant recovery of the phenotypes caused by APP
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