TY - JOUR
T1 - Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor protein via the MVB/lysosomal pathway
AU - González, Alexis E.
AU - Muñoz, Vanessa C.
AU - Cavieres, Viviana A.
AU - Bustamante, Hianara A.
AU - Cornejo, Víctor-Hugo
AU - Januário, Yunan C.
AU - González, Ibeth
AU - Hetz, Claudio
AU - daSilva, Luis L.
AU - Rojas-Fernández, Alejandro
AU - Hay, Ronald T.
AU - Mardones, Gonzalo A.
AU - Burgos, Patricia V.
N1 - This work was funded by the National Fund for Scientific and Technological Development (FONDECYT; Grants 1130929 to P.V.B., 1130710 to G.A.M., and 1140549 to C.H.); International Cooperation Program (PCI) of the National Commission for Scientific and Technological Research (CONICYT; Grants ECOS/CONICYT C14B03 to P.V.B., Fondo Newton-Picarte CONICYT DPI20140068 to P.V.B., and Fondo CONICYT Chile-Brazil 441921/2016-7 to C.H.); Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (FONDAP; Program 15150012 to C.H.); Millennium Institute (Grant P09-015-F to C.H.); Office of Naval Research-Global (ONR-G; N62909-16-1-2003 to C.H.); São Paulo Research Foundation (FAPESP; 2014/25812-0 to L.L.D.); Dirección de Investigación y Desarrollo–Universidad Austral de Chile (DID-UACh; Grant D-2013-07 to A.E.G. and D-2015-02 to H.A.B.); and Programa de Mejoramiento de la Calidad y la Equidad de la Educación (MECESUP; AUS 1203). A.E.G., V.A.C., and H.A.B. were supported by CONICYT fellowships 201110746, 21151194, and 21130315, respectively. Y.C.J. was supported by a Coordination for the Improvement of Higher Education Personnel (CAPES) fellowship from the Brazilian Ministry of Education. The use of the OMX microscope was funded by a Medical Research Council (MRC) Next Generation Optical Microscopy award (MR/K015869/1).
PY - 2017/6
Y1 - 2017/6
N2 - Brain regions affected by Alzheimer disease (AD) display well-recognized early neuropathologic features in the endolysosomal and autophagy systems of neurons, including enlargement of endosomal compartments, progressive accumulation of autophagic vacuoles, and lysosomal dysfunction. Although the primary causes of these disturbances are still under investigation, a growing body of evidence suggests that the amyloid precursor protein (APP) intracellular C-terminal fragment β (C99), generated by cleavage of APP by β-site APP cleaving enzyme 1 (BACE-1), is the primary cause of the endosome enlargement in AD and the earliest initiator of synaptic plasticity and long-term memory impairment. The aim of the present study was to evaluate the possible relationship between the endolysosomal degradation pathway and autophagy on the proteolytic processing and turnover of C99. We found that pharmacologic treatments that either inhibit autophagosome formation or block the fusion of autophagosomes to endolysosomal compartments caused an increase in C99 levels. We also found that inhibition of autophagosome formation by depletion of Atg5 led to higher levels of C99 and to its massive accumulation in the lumen of enlarged perinuclear, lysosomal-associated membrane protein 1 (LAMP1)-positive organelles. In contrast, activation of autophagosome formation, either by starvation or by inhibition of the mammalian target of rapamycin, enhanced lysosomal clearance of C99. Altogether, our results indicate that autophagosomes are key organelles to help avoid C99 accumulation preventing its deleterious effects.-González, A. E., Muñoz, V. C., Cavieres, V. A., Bustamante, H. A., Cornejo, V.-H., Januário, Y. C., González, I., Hetz, C., daSilva, L. L., Rojas-Fernández, A., Hay, R. T., Mardones, G. A., Burgos, P. V. Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor protein via the MVB/lysosomal pathway.
AB - Brain regions affected by Alzheimer disease (AD) display well-recognized early neuropathologic features in the endolysosomal and autophagy systems of neurons, including enlargement of endosomal compartments, progressive accumulation of autophagic vacuoles, and lysosomal dysfunction. Although the primary causes of these disturbances are still under investigation, a growing body of evidence suggests that the amyloid precursor protein (APP) intracellular C-terminal fragment β (C99), generated by cleavage of APP by β-site APP cleaving enzyme 1 (BACE-1), is the primary cause of the endosome enlargement in AD and the earliest initiator of synaptic plasticity and long-term memory impairment. The aim of the present study was to evaluate the possible relationship between the endolysosomal degradation pathway and autophagy on the proteolytic processing and turnover of C99. We found that pharmacologic treatments that either inhibit autophagosome formation or block the fusion of autophagosomes to endolysosomal compartments caused an increase in C99 levels. We also found that inhibition of autophagosome formation by depletion of Atg5 led to higher levels of C99 and to its massive accumulation in the lumen of enlarged perinuclear, lysosomal-associated membrane protein 1 (LAMP1)-positive organelles. In contrast, activation of autophagosome formation, either by starvation or by inhibition of the mammalian target of rapamycin, enhanced lysosomal clearance of C99. Altogether, our results indicate that autophagosomes are key organelles to help avoid C99 accumulation preventing its deleterious effects.-González, A. E., Muñoz, V. C., Cavieres, V. A., Bustamante, H. A., Cornejo, V.-H., Januário, Y. C., González, I., Hetz, C., daSilva, L. L., Rojas-Fernández, A., Hay, R. T., Mardones, G. A., Burgos, P. V. Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor protein via the MVB/lysosomal pathway.
KW - Alzheimer disease
KW - APP
KW - C99
KW - Multivesicular bodies
KW - Amphisome
KW - Proteostasis
U2 - 10.1096/fj.201600713R
DO - 10.1096/fj.201600713R
M3 - Article
C2 - 28254759
SN - 0892-6638
VL - 31
SP - 2446
EP - 2459
JO - FASEB Journal
JF - FASEB Journal
IS - 6
ER -