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|Title:||A novel fluorescent probe reveals starvation controls the commitment of amyloid precursor protein to the lysosome|
|Citation:||Biochimica et Biophysica Acta - Molecular Cell Research, 2017; 1864(10):1554-1565|
|Leanne K. Hein, Pirjo M. Apaja, Kathryn Hattersley, Randall H. Grose, Jianling Xie, Christopher G. Proud, Timothy J. Sargeant|
|Abstract:||Alzheimer's disease is the most important cause of dementia but there is no therapy that has been demonstrated to stop or slow disease progression. Amyloid precursor protein (APP) is the source of amyloid-β (Aβ), which aggregates in Alzheimer's disease to form toxic oligomeric species. The endo-lysosomal system can clear APP and Aβ from the cell if these molecular species are trafficked through to the lysosome. Currently, there are no easy methods available for the analysis of lysosomal APP trafficking. We therefore generated a fusion protein (tandem-fluorescent, or tf-APP) that allows detection of changes in APP trafficking using accessible techniques such as flow cytometry. This permits rapid analysis or screening of genes and compounds that alter APP processing in the cell. Using our novel molecular probe, we determined that starvation induces trafficking of APP and APP-carboxy-terminal fragments (APP-CTFs) to the degradative endo-lysosomal network. In line with this finding, suppression of mTOR signalling using AZD8055 also strongly induced trafficking of APP to the endo-lysosomal system. Remarkably, activation of mTOR signalling via RHEB over-expression inhibited the starvation-induced autophagy but did not affect trafficking of tf-APP. These results show tf-APP can be used to determine how APP is trafficked through the lysosomal system of the cell. This molecular probe is therefore useful for determining the molecular mechanism behind the commitment of APP to the degradative pathway or for screening compounds that can induce this effect. This is important as clearance of APP and APP-CTF provides an important potential therapeutic strategy for Alzheimer's disease.|
|Keywords:||Alzheimer's disease; Amyloid precursor protein; Endocytosis; Lysosome; Starvation; mTOR|
|Rights:||© 2017 Elsevier B.V. All rights reserved.|
|Appears in Collections:||Biochemistry publications|
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