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New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies

Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej, 10C, Aarhus 8000, Denmark
Institute of Biomedicine, Aarhus University, Bartholins Alle’, 6, Aarhus 8000, Denmark
Author to whom correspondence should be addressed.
Academic Editor: Amal Kaddoumi
Int. J. Mol. Sci. 2015, 16(12), 29446-29453;
Received: 2 October 2015 / Revised: 18 November 2015 / Accepted: 30 November 2015 / Published: 10 December 2015
(This article belongs to the Special Issue Amyloid-beta and Neurological Diseases)
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. View Full-Text
Keywords: Clathrin heavy chain; APP; 682YENPTY687; AICD; AP-2; Alzheimer’s disease Clathrin heavy chain; APP; 682YENPTY687; AICD; AP-2; Alzheimer’s disease
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Poulsen, E.T.; Larsen, A.; Zollo, A.; Jørgensen, A.L.; Sanggaard, K.W.; Enghild, J.J.; Matrone, C. New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies. Int. J. Mol. Sci. 2015, 16, 29446-29453.

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