title: Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein.
abstract: The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, α-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease-related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-β peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport.
authors.affiliation: From the Department of Neurology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Nguyen T
authors.initials: NT
authors.lastname: Tien
authors.affiliation: From the Department of Neurology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Ilker
authors.initials: I
authors.lastname: Karaca
authors.affiliation: From the Department of Neurology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Irfan Y
authors.initials: IY
authors.lastname: Tamboli
authors.affiliation: From the Department of Neurology, University of Bonn, 53127 Bonn, Germany jochen.walter@ukb.uni-bonn.de.
authors.forename: Jochen
authors.identifier: http://orcid.org/0000-0002-4678-2912
authors.initials: J
authors.lastname: Walter
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014199:Trehalose / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D014199:Trehalose; D058570:TOR Serine-Threonine Kinases; D053829:Amyloid Precursor Protein Secretases
keywords: amyloid precursor protein (APP); amyloid-β (Aβ); autophagy; endosome; intracellular trafficking; lysosome; trehalose