title: New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies.
abstract: The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer's disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y682 mutation in the 682YENPTY687 domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS) on hippocampal tissue extracts of three month-old mice incubated with either the 682YENPTY687 peptide, its mutated form, 682GENPTY687 or its phosphorylated form, 682pYENPTY687. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc) and its Adaptor Protein 2 (AP-2). Overall our results consolidate and refine the importance of Y682 in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies.
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej, 10C, Aarhus 8000, Denmark. etp@mbg.au.dk.
authors.forename: Ebbe Toftgaard
authors.initials: ET
authors.lastname: Poulsen
authors.affiliation: Institute of Biomedicine, Aarhus University, Bartholins Alle', 6, Aarhus 8000, Denmark. al@biomed.au.dk.
authors.forename: Agnete
authors.initials: A
authors.lastname: Larsen
authors.affiliation: Institute of Biomedicine, Aarhus University, Bartholins Alle', 6, Aarhus 8000, Denmark. zollo@biomed.au.dk.
authors.forename: Alen
authors.initials: A
authors.lastname: Zollo
authors.affiliation: Institute of Biomedicine, Aarhus University, Bartholins Alle', 6, Aarhus 8000, Denmark. alj@biomed.au.dk.
authors.forename: Arne L
authors.initials: AL
authors.lastname: Jørgensen
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej, 10C, Aarhus 8000, Denmark. kws@mbg.au.dk.
authors.forename: Kristian W
authors.initials: KW
authors.lastname: Sanggaard
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej, 10C, Aarhus 8000, Denmark. jje@mbg.au.dk.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Enghild
authors.affiliation: Institute of Biomedicine, Aarhus University, Bartholins Alle', 6, Aarhus 8000, Denmark. matrone@biomed.au.dk.
authors.forename: Carmela
authors.initials: C
authors.lastname: Matrone
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000302:isolation & purification / Q000502:physiology*; D000544:Alzheimer Disease / Q000188:drug therapy; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D015195:Drug Design; D055879:Gene Knock-In Techniques; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding
chemical_list: D033962:Adaptor Protein Complex 2; D016564:Amyloid beta-Protein Precursor
keywords: 682YENPTY687; AICD; AP-2; APP; Alzheimer’s disease; Clathrin heavy chain