Dissecting the two different modes of Amyloid precursor protein (APP) function: as soluble ligand and/or as synaptic adhesion molecule
Final Report Abstract
The amyloid precursor protein (APP), in addition to its pathogenic role as the precursor of bamyloid peptide (Ab), has important physiological functions in nervous system development, neuronal morphology and synaptic plasticity. In this proposal, we provide strong evidence that these functions are partly due to APPsα as a ligand and partly to APP's role as a synaptic adhesion protein. We demonstrated that APP and the paralogous proteins APLP1 and APLP2 (APLPs) occur as dimers at synapses and using a heterologous assay to study synaptogenesis, we also showed that APP family members can induce not only presynaptic but also postsynaptic differentiation, which both rely on the formation of APP trans-dimers. This was convincingly demonstrated using mutants that lack the ability to form trans-dimers (APP ΔE1) or suppress the secretion of APPs (APPΔS622). To validate these findings in vivo we generated knock-in mice carrying the APPΔS622 mutation. As expected, these knockin mice showed considerably reduced APPs secretion. When crossed onto an APLP2 background, unlike APP/APLP2 double knockout mice, neither early postnatal lethality, nor a reduction in spine density were observed. However, these mice exhibited impaired long-term potentiation (LTP), indicating a crucial role of endogenously produced APPsα for synaptic plasticity. In summary, our results show that APP promotes both presynaptic and postsynaptic differentiation through trans-synaptic dimerization, and that APPΔS622 mice, despite reduced APPs secretion, show largely normal basal synaptic transmission, but highly impaired synaptic plasticity. Further studies are needed to better understand the interplay between transmembrane APP, APPs, and other synaptic adhesion molecules and receptors.
Publications
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APPsα rescues impaired Ca2+homeostasis in APP- and APLP2-deficient hippocampal neurons. Proceedings of the National Academy of Sciences, 118(26).
Ludewig, Susann; Herrmann, Ulrike; Michaelsen-Preusse, Kristin; Metzdorf, Kristin; Just, Jennifer; Bold, Charlotte; Müller, Ulrike C. & Korte, Martin
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Fe65: A Scaffolding Protein of Actin Regulators. Cells, 10(7), 1599.
Augustin, Vanessa & Kins, Stefan
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Loss of all three APP family members during development impairs synaptic function and plasticity, disrupts learning, and causes an autism‐like phenotype. The EMBO Journal, 40(12).
Steubler, Vicky; Erdinger, Susanne; Back, Michaela K.; Ludewig, Susann; Fässler, Dominique; Richter, Max; Han, Kang; Slomianka, Lutz; Amrein, Irmgard; von Engelhardt, Jakob; Wolfer, David P.; Korte, Martin & Müller, Ulrike C.
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Lack of APLP1 leads to subtle alterations in neuronal morphology but does not affect learning and memory. Frontiers in Molecular Neuroscience, 15.
Erdinger, Susanne; Amrein, Irmgard; Back, Michaela; Ludewig, Susann; Korte, Martin; von Engelhardt, Jakob; Wolfer, David P. & Müller, Ulrike C.
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APP family member dimeric complexes are formed predominantly in synaptic compartments. Cell & Bioscience, 13(1).
Schilling, Sandra; August, Alexander; Meleux, Mathieu; Conradt, Carolin; Tremmel, Luisa M.; Teigler, Sandra; Adam, Virginie; Müller, Ulrike C.; Koo, Edward H.; Kins, Stefan & Eggert, Simone
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Differential effects of familial Alzheimer’s disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity. Acta Neuropathologica Communications, 11(1).
Schilling, Sandra; Pradhan, Ajay; Heesch, Amelie; Helbig, Andrea; Blennow, Kaj; Koch, Christian; Bertgen, Lea; Koo, Edward H.; Brinkmalm, Gunnar; Zetterberg, Henrik; Kins, Stefan & Eggert, Simone
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Zinc and copper effect mechanical cell adhesion properties of the amyloid precursor protein. Biological Chemistry, 405(11-12), 701-710.
August, Alexander; Hartmann, Sabrina; Schilling, Sandra; Müller-Renno, Christine; Begic, Tarik; Pierik, Antonio J.; Ziegler, Christiane & Kins, Stefan
