Physiological APP processing is required for synaptic plasticity and cognition
8 affiliations
- 1Department of Functional Genomics, Institute of Pharmacy and Molecular Biotechnology (IPMB), Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
- 2Institute for Cell- and Neurobiology, TU Braunschweig, Braunschweig, Germany
- 3Department of Neuroanatomy, Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany
- 4Department of Anatomy, University of Zürich, Zürich, Switzerland
- 5Institute of Human Movement Sciences and Sport, D-HEST, ETH Zürich, Zürich, Switzerland
- 6Focus Program Translational Neurosciences (FTN), University Medical Center of the Johannes Gutenberg University Mainz, Institute of Pathophysiology, Mainz, Germany
- 7Institute for Clinical Neuroanatomy, Goethe University Frankfurt, Frankfurt/Main, Germany
- 8Neuroinflammation and Neurodegeneration Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
Abstract
While the accumulation of Aβ peptides, derived by proteolytic cleavage from the amyloid precursor protein APP, constitutes a hallmark of Alzheimer’s disease, the question of whether endogenous, physiological APP processing serves an essential role for normal brain function(s) has remained elusive. Here, we modified the mouse APP locus to delete the endogenous α- and β-secretase sites (APP residues S592-G621) while preserving the transmembrane topology and the APP C-terminus. These novel knockin mice (termed APPΔS622) lack APPsα, APPβ, and Aβ production and show only minimal soluble APPs shedding. These APPΔS622 mice provide a unique model to distinguish between functions mediated by unprocessed cell surface APP involved in synaptic adhesion or by proteolytic fragments. Strikingly, APPΔS622 mice exhibit pronounced impairments in both long-term potentiation (LTP) and homeostatic forms of synaptic plasticity. Extracellular field recordings revealed significant deficits in hippocampal LTP, associated with a reduced density of mature spines and reduced spine head size. LTP deficits could be restored by APPsα application, suggesting a requirement for non-amyloidogenic APP processing for LTP. In addition, APPΔS622 mice lacking endogenous Aβ displayed a lack of homeostatic synaptic scaling in response to network impairment that could be specifically rescued by exogenous Aβ. Importantly, these deficits in different forms of synaptic plasticity also led to impairments in cognitive behavior. In summary, our findings reveal an essential role of physiological APP processing products to differentially regulate complementary forms of synaptic plasticity that are critical for network stability, normal brain function and cognition.
Related
- Bassoon is required for adult ocular dominance plasticity and experience-induced changes in synapsin phosphorylation in visual cortex
- Genetic and Molecular Mechanisms of Synaptic Plasticity in Perioperative Delirium: From Neuroinflammation to Circuit Dysfunction and Recovery
- Myelin Maintenance and Addition Regulate Synaptic Plasticity in the Adult Mouse Cortex
- A physiological Na+ signal activates mitochondrial PINK1 to couple synaptic depression to caspase-3-dependent spine pruning
- Astrocytes Control Cocaine-Induced Synaptic Plasticity and Reward Through the Matricellular Protein Hevin
BibTeX
@article{kilian2026physiological,
title = {{Physiological APP processing is required for synaptic plasticity and cognition}},
author = {Lara Kilian and Verena Bengelsdorff and Jennifer Just and Sebastian Stork and Christos Galanis and Marija Banicevic and Irmgard Amrein and Michaela Back and Tassilo Jungenitz and Meike Fellenz and Jakob von Engelhardt and Thomas Deller and David P. Wolfer and Andreas Vlachos and Martin Korte and Ulrike C. Müller},
journal = {Cell Death \& Disease},
year = {2026},
month = nov,
doi = {10.1038/s41419-026-09378-6},
url = {https://doi.org/10.1038/s41419-026-09378-6},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Physiological APP processing is required for synaptic plasticity and cognition
AU - Lara Kilian
AU - Verena Bengelsdorff
AU - Jennifer Just
AU - Sebastian Stork
AU - Christos Galanis
AU - Marija Banicevic
AU - Irmgard Amrein
AU - Michaela Back
AU - Tassilo Jungenitz
AU - Meike Fellenz
AU - Jakob von Engelhardt
AU - Thomas Deller
AU - David P. Wolfer
AU - Andreas Vlachos
AU - Martin Korte
AU - Ulrike C. Müller
PY - 2026
DA - 2026/11/04
JO - Cell Death & Disease
DO - 10.1038/s41419-026-09378-6
UR - https://doi.org/10.1038/s41419-026-09378-6
AB - While the accumulation of Aβ peptides, derived by proteolytic cleavage from the amyloid precursor protein APP, constitutes a hallmark of Alzheimer’s disease, the question of whether endogenous, physiological APP processing serves an essential role for normal brain function(s) has remained elusive. Here, we modified the mouse APP locus to delete the endogenous α- and β-secretase sites (APP residues S592-G621) while preserving the transmembrane topology and the APP C-terminus. These novel knockin mice (termed APPΔS622) lack APPsα, APPβ, and Aβ production and show only minimal soluble APPs shedding. These APPΔS622 mice provide a unique model to distinguish between functions mediated by unprocessed cell surface APP involved in synaptic adhesion or by proteolytic fragments. Strikingly, APPΔS622 mice exhibit pronounced impairments in both long-term potentiation (LTP) and homeostatic forms of synaptic plasticity. Extracellular field recordings revealed significant deficits in hippocampal LTP, associated with a reduced density of mature spines and reduced spine head size. LTP deficits could be restored by APPsα application, suggesting a requirement for non-amyloidogenic APP processing for LTP. In addition, APPΔS622 mice lacking endogenous Aβ displayed a lack of homeostatic synaptic scaling in response to network impairment that could be specifically rescued by exogenous Aβ. Importantly, these deficits in different forms of synaptic plasticity also led to impairments in cognitive behavior. In summary, our findings reveal an essential role of physiological APP processing products to differentially regulate complementary forms of synaptic plasticity that are critical for network stability, normal brain function and cognition.
SN - 2041-4889
ER -