TY - JOUR
T1 - Aβ Secretion and Plaque Formation Depend on Autophagy
AU - Nilsson, Per
AU - Loganathan, Krishnapriya
AU - Sekiguchi, Misaki
AU - Matsuba, Yukio
AU - Hui, Kelvin
AU - Tsubuki, Satoshi
AU - Tanaka, Motomasa
AU - Iwata, Nobuhisa
AU - Saito, Takashi
AU - Saido, Takaomi C.
N1 - Funding Information:
We thank Keiji Tanaka and Shigeyoshi Itohara for generously providing Atg7 flox/flox and CamKII-Cre mice, respectively. We acknowledge the members of the PNS lab, Jiro Takano, Ko Sato, Kenichi Nagata, Naomasa Kakiya, Shoko Hashimoto, Hayato Isshiki, Kaori Tsukakoshi, Karin Sörgjerd, Emi Hosoki, Ryo Fujioka, Naomi Yamazaki, Yuya Tomita, and Yukiko Nagai. We appreciate the kind gift of the HDAC6 antibody from Tso-Pang Yao. This project was financially supported by research grants from Swedish Research Council, Sweden; RIKEN Brain Science Institute; Ministry of Education, Sports, Science and Technology, Japan; and Ministry of Health, Labour and Welfare, Japan.
PY - 2013/10/17
Y1 - 2013/10/17
N2 - Alzheimer@s disease (AD) is a neurodegenerative disease biochemically characterized by aberrant protein aggregation, including amyloid beta (Aβ) peptide accumulation. Protein aggregates in the cell are cleared by autophagy, a mechanism impaired in AD. To investigate the role of autophagy in Aβ pathology invivo, we crossed amyloid precursor protein (APP) transgenic mice with mice lacking autophagy in excitatory forebrain neurons obtained by conditional knockout of autophagy-related protein 7. Remarkably, autophagy deficiency drastically reduced extracellular Aβ plaque burden. This reduction of Aβ plaque load was due to inhibition of Aβ secretion, which led to aberrant intraneuronal Aβ accumulation in the perinuclear region. Moreover, autophagy-deficiency-induced neurodegeneration was exacerbated by amyloidosis, which together severely impaired memory. Our results establish a function for autophagy in Aβ metabolism: autophagy influences secretion of Aβ to the extracellular space and thereby directly affects Aβ plaque formation, a pathological hallmark of AD
AB - Alzheimer@s disease (AD) is a neurodegenerative disease biochemically characterized by aberrant protein aggregation, including amyloid beta (Aβ) peptide accumulation. Protein aggregates in the cell are cleared by autophagy, a mechanism impaired in AD. To investigate the role of autophagy in Aβ pathology invivo, we crossed amyloid precursor protein (APP) transgenic mice with mice lacking autophagy in excitatory forebrain neurons obtained by conditional knockout of autophagy-related protein 7. Remarkably, autophagy deficiency drastically reduced extracellular Aβ plaque burden. This reduction of Aβ plaque load was due to inhibition of Aβ secretion, which led to aberrant intraneuronal Aβ accumulation in the perinuclear region. Moreover, autophagy-deficiency-induced neurodegeneration was exacerbated by amyloidosis, which together severely impaired memory. Our results establish a function for autophagy in Aβ metabolism: autophagy influences secretion of Aβ to the extracellular space and thereby directly affects Aβ plaque formation, a pathological hallmark of AD
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U2 - 10.1016/j.celrep.2013.08.042
DO - 10.1016/j.celrep.2013.08.042
M3 - Article
C2 - 24095740
AN - SCOPUS:84885864424
SN - 2211-1247
VL - 5
SP - 61
EP - 69
JO - Cell Reports
JF - Cell Reports
IS - 1
ER -