Macroautophagy Is Not Directly Involved in the Metabolism of Amyloid
Precursor Protein |
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Authors: | Barry Boland David A Smith Declan Mooney Sonia S Jung Dominic M Walsh Frances M Platt |
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Institution: | From the ‡Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.;¶Centocor Research and Development Inc., Radnor, Pennsylvania 19087, and ;the §Department of Pharmacology, University of Oxford, Oxford OX13QT, United Kingdom |
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Abstract: | Alterations in the metabolism of amyloid precursor protein (APP) are believed to
play a central role in Alzheimer disease pathogenesis. Burgeoning data indicate
that APP is proteolytically processed in endosomal-autophagic-lysosomal
compartments. In this study, we used both in vivo and
in vitro paradigms to determine whether alterations in
macroautophagy affect APP metabolism. Three mouse models of glycosphingolipid
storage diseases, namely Niemann-Pick type C1, GM1 gangliosidosis, and Sandhoff
disease, had mTOR-independent increases in the autophagic vacuole
(AV)-associated protein, LC3-II, indicative of impaired lysosomal flux. APP
C-terminal fragments (APP-CTFs) were also increased in brains of the three mouse
models; however, discrepancies between LC3-II and APP-CTFs were seen between
primary (GM1 gangliosidosis and Sandhoff disease) and secondary (Niemann-Pick
type C1) lysosomal storage models. APP-CTFs were proportionately higher than
LC3-II in cerebellar regions of GM1 gangliosidosis and Sandhoff disease,
although LC3-II increased before APP-CTFs in brains of NPC1 mice. Endogenous
murine Aβ40 from RIPA-soluble extracts was increased in brains of all
three mice. The in vivo relationship between AV and APP-CTF
accumulation was also seen in cultured neurons treated with agents that impair
primary (chloroquine and leupeptin + pepstatin) and secondary (U18666A
and vinblastine) lysosomal flux. However, Aβ secretion was unaffected by
agents that induced autophagy (rapamycin) or impaired AV clearance, and
LC3-II-positive AVs predominantly co-localized with degradative LAMP-1-positive
lysosomes. These data suggest that neuronal macroautophagy does not directly
regulate APP metabolism but highlights the important anti-amyloidogenic role of
lysosomal proteolysis in post-secretase APP-CTF catabolism. |
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Keywords: | Alzheimer Disease Amyloid Autophagy Endocytosis Lysosomal Storage Disease Lysosomes Neurobiology Neuron Secretases Storage Diseases |
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