APLP1 is a synaptic cell adhesion molecule, supporting maintenance of dendritic spines and basal synaptic transmission
- Sandra Schilling1,*,
- Annika Mehr2,*,
- Susann Ludewig3,
- Jonathan Stephan4,
- Marius Zimmermann1,
- Alexander August1,
- Paul Strecker1,
- Martin Korte4,5,
- Edward H. Koo6,
- Ulrike Müller2,*,
- Stefan Kins1,*, and
- Simone Eggert1,*
- 1Department of Human Biology and Human Genetics, University of Kaiserslautern, 67663 Kaiserslautern, Germany
- 2Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany
- 3Department of Cellular Neurobiology, TU Braunschweig, Zoological Institute, 38106 Braunschweig, Germany
- 4Department of Animal Physiology, University of Kaiserslautern, 67663 Kaiserslautern, Germany
- 5Helmholtz Centre for Infection Research, AG NIND, 38124 Braunschweig, Germany
- 6Department of Neuroscience, University of California San Diego (UCSD), La Jolla, CA 92093-0662, USA
- Corresponding author's: Simone Eggert: s.eggert{at}biologie.uni-kl.de; Stefan Kins: s.kins{at}biologie.uni-kl.de, Department of Human Biology and Human Genetics, University of Kaiserslautern, Erwin-Schrödinger-Str. 13, 67663 Kaiserslautern
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↵* the indicated first and last authors contributed equally to this work
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Author contributions: S.S., J.S., U.M., S.K., and S.E. designed research; S.S., A.M., S.L., J.S., M.Z., A.A., P.S., and S.E. performed research; S.S., A.M., S.L., J.S., M.Z., A.A., M.K., E.H.H.K., U.M., S.K., and S.E. analyzed data; S.S., J.S., M.K., E.H.H.K., U.M., S.K., and S.E. wrote the paper.
Abstract
The amyloid precursor protein (APP), a key player in Alzheimer's disease, belongs to the family of synaptic adhesion molecules (SAM's) due to its impact on synapse formation and synaptic plasticity. These functions are mediated by both, the secreted ectodomain (sAPP) that acts as a neurotrophic factor and full-length APP forming trans-cellular dimers. Two homologues of APP exist in mammals, the APP like proteins, APLP1 and APLP2, exhibiting partly overlapping functions to APP. Here we tested if APLP1 and APLP2 also show features of SAMs. We found that all three family members were upregulated during postnatal development coinciding with synaptogenesis. We observed pre- and postsynaptic localization of all APP family members and could show that heterologous expression of APLP1 or APLP2 in non-neuronal cells induces presynaptic differentiation in contacting axons of co-cultured neurons, similar to APP and other SAMs. Moreover, APP/APLPs all bind to synaptic signaling molecules, such as MINT/X11. Furthermore, we report that aged APLP1 knockout mice show impaired basal transmission and a reduced mEPSCs frequency, likely resulting from reduced spine density. This demonstrates an essential non-redundant function of APLP1 at the synapse. In comparison to APP, APLP1 exhibits increased transcellular binding and elevated cell-surface levels, due to reduced endocytosis. In conclusion, our results establish that APLPs show typical features of SAMs, and indicate that increased surface expression, as observed for APLP1, is essential for proper synapse formation in vitro and synapse maintenance in vivo.
SIGNIFICANCE STATEMENT
According to the Amyloid-Cascade-Hypothesis Alzheimer's Disease is caused by the accumulation of Aβ peptides derived from sequential cleavage of the Amyloid Precursor Protein (APP) by BACE1 and γ-secretase. Here we show that all mammalian APP family members (APP, APLP1, APLP2) exhibit synaptogenic activity, involving trans-synaptic dimerization, similar to other synaptic cell adhesion molecules (SAMs), such as Neuroligin/Neurexin. Importantly, our study revealed that loss of APLP1, which is one of the major substrates of BACE1, causes reduced spine density in aged mice. As some therapeutic interventions target APP processing (e.g. BACE inhibitors), those strategies may alter APP/APLPs physiological function. This should be taken under account for development of pharmaceutical treatments of Alzheimer's disease.
Footnotes
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We thank Dagmar Gross, Luigina Hanke, Carolin Thomas, Tina Kehrwald and Jennifer Winkelhoff for excellent technical assistance. Furthermore, we would like to thank Dr. Harald Witte and Prof. Peter Scheiffele for kindly providing the Neuroligin1 plasmid. Additionally, we thank Prof. Suzuki for kindly providing X11β and X11γ plasmids and we thank Dr. Anita Szodorai for sciatic and optical nerve preparations. We thank DFG for funding in context of FOR 1332 to SK, UM, MK. UM was supported by the ERA-Net Neuron (01EW1305A). SE was supported by funding of the TU Nachwuchsring. The authors declare no competing financial interests.
- Received June 10, 2016.
- Revision received February 22, 2017.
- Accepted March 24, 2017.
- Copyright © 2017 the authors
