{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T14:20:19Z","timestamp":1784989219580,"version":"3.55.0"},"reference-count":65,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Galimedix Therapeutics Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Soluble oligomeric forms of Amyloid-\u03b2 (A\u03b2) are considered the major toxic species leading to the neurodegeneration underlying Alzheimer\u2019s disease (AD). Therefore, drugs that prevent oligomer formation might be promising. The atypical dipeptide GAL-201 is orally bioavailable and interferes as a modulator of A\u03b2 aggregation. It binds to aggregation-prone, misfolded A\u03b2 monomers with high selectivity and affinity, thereby preventing the formation of toxic oligomers. Here, we demonstrate that the previously observed protective effect of GAL-201 on synaptic plasticity occurs irrespective of shortages and post-translational modifications (tested isoforms: A\u03b21\u201342, A\u03b2(p3-42), A\u03b21\u201340 and 3NTyr(10)-A\u03b2). Interestingly, the neuroprotective activity of a single dose of GAL-201 was still present after one week and correlated with a prevention of A\u03b2-induced spine loss. Furthermore, we could observe beneficial effects on spine morphology as well as the significantly reduced activation of proinflammatory microglia and astrocytes in the presence of an A\u03b21\u201342-derived toxicity. In line with these in vitro data, GAL-201 additionally improved hippocampus-dependent spatial learning in the \u201ctgArcSwe\u201d AD mouse model after a single subcutaneous administration. By this means, we observed changes in the deposition pattern: through the clustering of misfolded monomers as off-pathway non-toxic A\u03b2 agglomerates, toxic oligomers are removed. Our results are in line with previously collected preclinical data and warrant the initiation of Investigational New Drug (IND)-enabling studies for GAL-201. By demonstrating the highly efficient detoxification of \u03b2-sheet monomers, leading to the neutralization of A\u03b2 oligomer toxicity, GAL-201 represents a promising drug candidate against A\u03b2-derived pathophysiology present in AD.<\/jats:p>","DOI":"10.3390\/ijms26094167","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T11:48:33Z","timestamp":1745840913000},"page":"4167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["GAL-201 as a Promising Amyloid-\u03b2-Targeting Small-Molecule Approach for Alzheimer\u2019s Disease Treatment: Consistent Effects on Synaptic Plasticity, Behavior and Neuroinflammation"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1296-7495","authenticated-orcid":false,"given":"Katrin","family":"Riemann","sequence":"first","affiliation":[{"name":"Galimedix Therapeutics Inc., 3704 Calvend Lane, Kensington, MD 20895, USA"},{"name":"Department of Anesthesiology and Intensive Care, School of Medicine and Health, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeldrik","family":"von Ahsen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, School of Medicine and Health, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9360-0429","authenticated-orcid":false,"given":"Tamara","family":"B\u00f6hm","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, School of Medicine and Health, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7054-9566","authenticated-orcid":false,"given":"Martin","family":"Schlegel","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, School of Medicine and Health, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2472-3556","authenticated-orcid":false,"given":"Matthias","family":"Kreuzer","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, School of Medicine and Health, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0132-9591","authenticated-orcid":false,"given":"Thomas","family":"Fenzl","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, School of Medicine and Health, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann","family":"Russ","sequence":"additional","affiliation":[{"name":"Galimedix Therapeutics Inc., 3704 Calvend Lane, Kensington, MD 20895, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher G.","family":"Parsons","sequence":"additional","affiliation":[{"name":"Galimedix Therapeutics Inc., 3704 Calvend Lane, Kensington, MD 20895, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1698-4257","authenticated-orcid":false,"given":"Gerhard","family":"Rammes","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, School of Medicine and Health, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/S0006-291X(84)80190-4","article-title":"Alzheimer\u2019s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein","volume":"120","author":"Glenner","year":"1984","journal-title":"Biochem. 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