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 - Publisher Copyright:
© FASEB.
PY - 2017/6
Y1 - 2017/6
N2 - Brain regions affected by Alzheimer disease (AD) displaywell-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 b (C99), generated by cleavage of APP by b-site APP cleaving enzyme 1 (BACE-1), is the primary cause of the endosome enlargement inADand the earliest initiator of synaptic plasticity and long-termmemory impairment. The aimof 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 autophagosomeformationorblock the fusionof 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 helpavoidC99 accumulation preventing its deleterious effects.
AB - Brain regions affected by Alzheimer disease (AD) displaywell-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 b (C99), generated by cleavage of APP by b-site APP cleaving enzyme 1 (BACE-1), is the primary cause of the endosome enlargement inADand the earliest initiator of synaptic plasticity and long-termmemory impairment. The aimof 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 autophagosomeformationorblock the fusionof 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 helpavoidC99 accumulation preventing its deleterious effects.
KW - APP
KW - Alzheimer disease
KW - Amphisome
KW - C99
KW - Multivesicular bodies
KW - Proteostasis
UR - http://www.scopus.com/inward/record.url?scp=85020309030&partnerID=8YFLogxK
U2 - 10.1096/fj.201600713R
DO - 10.1096/fj.201600713R
M3 - Article
C2 - 28254759
AN - SCOPUS:85020309030
SN - 0892-6638
VL - 31
SP - 2446
EP - 2459
JO - FASEB Journal
JF - FASEB Journal
IS - 6
ER -