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In the search for a preventive treatment strategy, we tested the effect of scavenging A\u03b2 peptides before A\u03b2 plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an A\u03b2 binding anticalin protein (A\u03b2-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of \u03b2-amyloidosis. Our results suggest that the sole targeting of A\u03b2 monomers is sufficient for the hyperactivity-suppressing effect of the A\u03b2-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the A\u03b2-anticalin-dependent depletion of naturally secreted A\u03b2 monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that A\u03b2 monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.<\/jats:p>","DOI":"10.1038\/s41467-024-50153-y","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T18:01:38Z","timestamp":1720634498000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["\u03b2-amyloid monomer scavenging by an anticalin protein prevents neuronal hyperactivity in mouse models of Alzheimer\u2019s Disease"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4537-7381","authenticated-orcid":false,"given":"Benedikt","family":"Zott","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"N\u00e4stle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7774-4062","authenticated-orcid":false,"given":"Christine","family":"Grienberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0026-8026","authenticated-orcid":false,"given":"Felix","family":"Unger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3475-2396","authenticated-orcid":false,"given":"Manuel M.","family":"Knauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7755-4691","authenticated-orcid":false,"given":"Christian","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aylin","family":"Keskin-Dargin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Feuerbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4416-7553","authenticated-orcid":false,"given":"Marc Aurel","family":"Busche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5717-498X","authenticated-orcid":false,"given":"Arne","family":"Skerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9548-2676","authenticated-orcid":false,"given":"Arthur","family":"Konnerth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,10]]},"reference":[{"key":"50153_CR1","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","volume":"8","author":"DJ Selkoe","year":"2016","unstructured":"Selkoe, D. 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