Alkalizing Drugs Induce Accumulation of Amyloid Precursor Protein By-products in Luminal Vesicles of Multivesicular Bodies
Amyloid precursor protein (APP) metabolism is central to the pathogenesis of Alzheimer disease. We showed recently that the amyloid intracellular domain (AICD), which is released by γ-secretase cleavage of APP C-terminal fragments (CTFs), is strongly increased in cells treated with alkalizing drugs (Vingtdeux, V., Hamdane, M., Bégard, S., Loyens, A., Delacourte, A., Beauvillain, J.-C., Buée, L., Marambaud, P., and Sergeant, N. (2007) Neurobiol. Dis. 25, 686–696). Herein, we aimed to determine the cell compartment in which AICD accumulates. We show that APP-CTFs and AICD are present in multivesicular structures. Multivesicular bodies contain intraluminal vesicles (known as exosomes) when released in the extracellular space. We demonstrate that APP, APP-CTFs, and AICD are integrated and secreted within exosomes in differentiated neuroblastoma and primary neuronal culture cells. Together with recent data showing that amyloid-β is also found in exosomes, our data show that multivesicular bodies are essential organelles for APP metabolism and that all APP metabolites can be secreted in the extracellular space. Amyloid precursor protein (APP) metabolism is central to the pathogenesis of Alzheimer disease. We showed recently that the amyloid intracellular domain (AICD), which is released by γ-secretase cleavage of APP C-terminal fragments (CTFs), is strongly increased in cells treated with alkalizing drugs (Vingtdeux, V., Hamdane, M., Bégard, S., Loyens, A., Delacourte, A., Beauvillain, J.-C., Buée, L., Marambaud, P., and Sergeant, N. (2007) Neurobiol. Dis. 25, 686–696). Herein, we aimed to determine the cell compartment in which AICD accumulates. We show that APP-CTFs and AICD are present in multivesicular structures. Multivesicular bodies contain intraluminal vesicles (known as exosomes) when released in the extracellular space. We demonstrate that APP, APP-CTFs, and AICD are integrated and secreted within exosomes in differentiated neuroblastoma and primary neuronal culture cells. Together with recent data showing that amyloid-β is also found in exosomes, our data show that multivesicular bodies are essential organelles for APP metabolism and that all APP metabolites can be secreted in the extracellular space. Amyloid precursor protein (APP) 3The abbreviations APP, amyloid precursor C-terminal amyloid intracellular multivesicular amyloid precursor 3The abbreviations APP, amyloid precursor C-terminal amyloid intracellular multivesicular amyloid precursor metabolism is central to Alzheimer amyloid of Alzheimer are of amyloid-β that APP APP is by to C-terminal fragments APP-CTFs and the amyloid intracellular domain all APP-CTFs Neurobiol. Dis. N. N. Neurobiol. Dis. of that AICD is of APP, and AICD is and We showed recently that AICD is strongly increased with alkalizing that the AICD N. Neurobiol. 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