β-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer’s Disease

Benedikt Zott (), Lea Nästle, Christine Grienberger, Felix Unger, Manuel M. Knauer, Christian Wolf, Aylin Keskin-Dargin, Anna Feuerbach, Marc Aurel Busche, Arne Skerra () and Arthur Konnerth ()
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Benedikt Zott: Technical University of Munich
Lea Nästle: Technical University of Munich
Christine Grienberger: Technical University of Munich
Felix Unger: Technical University of Munich
Manuel M. Knauer: Technical University of Munich
Christian Wolf: Technical University of Munich
Aylin Keskin-Dargin: Technical University of Munich
Anna Feuerbach: Technical University of Munich
Marc Aurel Busche: Technical University of Munich
Arne Skerra: Technical University of Munich
Arthur Konnerth: Technical University of Munich

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Hyperactivity mediated by synaptotoxic β-amyloid (Aβ) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer’s disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aβ peptides before Aβ plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an Aβ binding anticalin protein (Aβ-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of β-amyloidosis. Our results suggest that the sole targeting of Aβ monomers is sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the Aβ-anticalin-dependent depletion of naturally secreted Aβ monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that Aβ monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.

Date: 2024
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DOI: 10.1038/s41467-024-50153-y

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