{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T09:23:12Z","timestamp":1777540992993,"version":"3.51.4"},"reference-count":76,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T00:00:00Z","timestamp":1688601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The introduction of anti-amyloid monoclonal antibodies against Alzheimer\u2019s disease (AD) is of high importance. However, even though treated patients show very little amyloid pathology, there is only a modest effect on the rate of cognitive decline. Although this effect can possibly increase over time, there is still a need for alternative treatments that will improve cognitive function in patients with AD. Therefore, the purpose of this study was to characterize the triazinetrione ACD856, a novel pan-Trk positive allosteric modulator, in multiple models to address its neuroprotective and potential disease-modifying effects. The pharmacological effect of ACD856 was tested in recombinant cell lines, primary cortical neurons, or animals. We demonstrate that ACD856 enhanced NGF-induced neurite outgrowth, increased the levels of the pre-synaptic protein SNAP25 in PC12 cells, and increased the degree of phosphorylated TrkB in SH-SY5Y cells. In primary cortical neurons, ACD856 led to increased levels of phospho-ERK1\/2, showed a neuroprotective effect against amyloid-beta or energy-deprivation-induced neurotoxicity, and increased the levels of brain-derived neurotrophic factor (BDNF). Consequently, administration of ACD856 resulted in a significant increase in BDNF in the brains of 21 months old mice. Furthermore, repeated administration of ACD856 resulted in a sustained anti-depressant effect, which lasted up to seven days, suggesting effects that go beyond merely symptomatic effects. In conclusion, the results confirm ACD856 as a cognitive enhancer, but more importantly, they provide substantial in vitro and in vivo evidence of neuroprotective and long-term effects that contribute to neurotrophic support and increased neuroplasticity. Presumably, the described effects of ACD856 may improve cognition, increase resilience, and promote neurorestorative processes, thereby leading to a healthier brain in patients with AD.<\/jats:p>","DOI":"10.3390\/ijms241311159","type":"journal-article","created":{"date-parts":[[2023,7,7]],"date-time":"2023-07-07T01:41:36Z","timestamp":1688694096000},"page":"11159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"given":"Cristina","family":"Parrado Fernandez","sequence":"first","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 141 57 Huddinge, Sweden"},{"name":"Division of Neuroscience, Care and Society, Department of Neurogeriatrics, Karolinska Institutet, 171 77 Solna, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanja","family":"Juric","sequence":"additional","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 141 57 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Backlund","sequence":"additional","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 141 57 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e4rta","family":"Dahlstr\u00f6m","sequence":"additional","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 141 57 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nather","family":"Madjid","sequence":"additional","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 141 57 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica","family":"Lidell","sequence":"additional","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 141 57 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Azita","family":"Rasti","sequence":"additional","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 141 57 Huddinge, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-456X","authenticated-orcid":false,"given":"Johan","family":"Sandin","sequence":"additional","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 141 57 Huddinge, Sweden"},{"name":"Division of Neuroscience, Care and Society, Department of Neurogeriatrics, Karolinska Institutet, 171 77 Solna, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1811-2823","authenticated-orcid":false,"given":"Gunnar","family":"Nordvall","sequence":"additional","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 141 57 Huddinge, Sweden"},{"name":"Division of Neuroscience, Care and Society, Department of Neurogeriatrics, Karolinska Institutet, 171 77 Solna, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8384-1547","authenticated-orcid":false,"given":"Pontus","family":"Forsell","sequence":"additional","affiliation":[{"name":"AlzeCure Pharma AB, H\u00e4lsov\u00e4gen 7, 141 57 Huddinge, Sweden"},{"name":"Division of Neuroscience, Care and Society, Department of Neurogeriatrics, Karolinska Institutet, 171 77 Solna, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/j.1749-6632.1952.tb26548.x","article-title":"Effects of mouse tumor transplantation on the nervous system","volume":"55","year":"1952","journal-title":"Ann. 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