APLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission.
Average rating
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Star rating
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Authors
Schilling, SandraMehr, Annika
Ludewig, Susann
Stephan, Jonathan
Zimmermann, Marius
August, Alexander
Strecker, Paul
Korte, Martin
Koo, Edward H
Müller, Ulrike C
Kins, Stefan
Eggert, Simone
Issue Date
2017-05-24
Metadata
Show full item recordAbstract
The amyloid precursor protein (APP), a key player in Alzheimer's disease, belongs to the family of synaptic adhesion molecules (SAMs) due to its impact on synapse formation and synaptic plasticity. These functions are mediated by both the secreted APP ectodomain that acts as a neurotrophic factor and full-length APP forming trans-cellular dimers. Two homologs of APP exist in mammals: the APP like proteins APLP1 and APLP2, exhibiting functions that partly overlap with those of APP. Here we tested whether 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 presynaptic 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 cocultured 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 knock-out mice show impaired basal transmission and a reduced mEPSC frequency, likely resulting from reduced spine density. This demonstrates an essential nonredundant function of APLP1 at the synapse. Compared to APP, APLP1 exhibits increased trans-cellular 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 vivoSIGNIFICANCE 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 β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Here we show that all mammalian APP family members (APP, APLP1, and APLP2) exhibit synaptogenic activity, involving trans-synaptic dimerization, similar to other synaptic cell adhesion molecules, such as Neuroligin/Neurexin. Importantly, our study revealed that the loss of APLP1, which is one of the major substrates of BACE1, causes reduced spine density in aged mice. Because some therapeutic interventions target APP processing (e.g., BACE inhibitors), those strategies may alter APP/APLP physiological function. This should be taken into account for the development of pharmaceutical treatments of Alzheimer's disease.Citation
APLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission. 2017, 37 (21):5345-5365 J. Neurosci.Affiliation
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.PubMed ID
28450540Type
ArticleLanguage
enISSN
1529-2401ae974a485f413a2113503eed53cd6c53
10.1523/JNEUROSCI.1875-16.2017
Scopus Count
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
Related articles
- Differential role of APP and APLPs for neuromuscular synaptic morphology and function.
- Authors: Klevanski M, Saar M, Baumkötter F, Weyer SW, Kins S, Müller UC
- Issue date: 2014 Jul
- Amyloid precursor-like protein 1 (APLP1) exhibits stronger zinc-dependent neuronal adhesion than amyloid precursor protein and APLP2.
- Authors: Mayer MC, Schauenburg L, Thompson-Steckel G, Dunsing V, Kaden D, Voigt P, Schaefer M, Chiantia S, Kennedy TE, Multhaup G
- Issue date: 2016 Apr
- Deletion of the amyloid precursor-like protein 1 (APLP1) enhances excitatory synaptic transmission, reduces network inhibition but does not impair synaptic plasticity in the mouse dentate gyrus.
- Authors: Vnencak M, Paul MH, Hick M, Schwarzacher SW, Del Turco D, Müller UC, Deller T, Jedlicka P
- Issue date: 2015 Aug 1
- Rapid evolution of mammalian APLP1 as a synaptic adhesion molecule.
- Authors: Onodera W, Asahi T, Sawamura N
- Issue date: 2021 May 28
- The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.
- Authors: Klevanski M, Herrmann U, Weyer SW, Fol R, Cartier N, Wolfer DP, Caldwell JH, Korte M, Müller UC
- Issue date: 2015 Dec 9