{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T04:21:41Z","timestamp":1782361301754,"version":"3.54.5"},"reference-count":87,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,4,6]],"date-time":"2024-04-06T00:00:00Z","timestamp":1712361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"WisTa Laboratories Ltd.","award":["PAR1763"],"award-info":[{"award-number":["PAR1763"]}]},{"name":"WisTa Laboratories Ltd.","award":["NCN 2014\/15\/B\/NZ4\/05041"],"award-info":[{"award-number":["NCN 2014\/15\/B\/NZ4\/05041"]}]},{"name":"National Science Centre Poland","award":["PAR1763"],"award-info":[{"award-number":["PAR1763"]}]},{"name":"National Science Centre Poland","award":["NCN 2014\/15\/B\/NZ4\/05041"],"award-info":[{"award-number":["NCN 2014\/15\/B\/NZ4\/05041"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Basal forebrain cholinergic dysfunction, most likely linked with tau protein aggregation, is a characteristic feature of Alzheimer\u2019s disease (AD). Recent evidence suggests that tau protein is a putative target for the treatment of dementia, and the tau aggregation inhibitor, hydromethylthionine mesylate (HMTM), has emerged as a potential disease-modifying treatment. However, its efficacy was diminished in patients already receiving approved acetylcholinesterase inhibitors. In this study, we ask whether this negative interaction can also be mimicked in experimental tau models of AD and whether the underlying mechanism can be understood. From a previous age profiling study, 6-month-old line 1 (L1) tau transgenic mice were characterized by a severe reduction in several cholinergic markers. We therefore assessed whether long-term pre-exposure with the acetylcholinesterase inhibitor rivastigmine alone and in conjunction with the tau aggregation inhibitor HMTM can reverse cholinergic deficits in L1. Rivastigmine and HMTM, and combinations of the two compounds were administered orally for 11 weeks to both L1 and wild-type mice. The brains were sectioned with a focus on the basal forebrain, motor cortex and hippocampus. Immunohistochemical staining and quantification of choline acetyltransferase (ChAT), tyrosine kinase A (TrkA)-positive neurons and relative optical intensity (ROI) for vesicular acetylcholine transporter (VAChT), and acetylcholinesterase (AChE) reactivity confirmed reversal of the diminished cholinergic phenotype of interneurons (nucleus accumbens, striatum) and projection neurons (medial septum, nucleus basalis magnocellularis) by HMTM, to a greater extent than by rivastigmine alone in L1 mice. Combined administration did not yield additivity but, in most proxies, led to antagonistic effects in which rivastigmine decreased the benefits shown with HMTM alone. Local markers (VAChT and AChE) in target structures of the basal forebrain, motor cortex and hippocampal CA3 seemed to be normalized by HMTM, but not by rivastigmine or the combination of both drugs. HMTM, which was developed as a tau aggregation inhibitor, strongly decreased the tau load in L1 mice, however, not in combination with rivastigmine. Taken together, these data confirm a cholinergic phenotype in L1 tau transgenic mice that resembles the deficits observed in AD patients. This phenotype is reversible by HMTM, but at the same time appears to be subject to a homeostatic regulation induced by chronic pre-treatment with an acetylcholinesterase inhibitor, which interferes with the efficacy of HMTM. The strongest phenotypic reversal coincided with a normalization of the tau load in the cortex and hippocampus of L1, suggesting that tau accumulation underpins the loss of cholinergic markers in the basal forebrain and its projection targets.<\/jats:p>","DOI":"10.3390\/cells13070642","type":"journal-article","created":{"date-parts":[[2024,4,8]],"date-time":"2024-04-08T12:01:22Z","timestamp":1712577682000},"page":"642","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Neuroprotection of Cholinergic Neurons with a Tau Aggregation Inhibitor and Rivastigmine in an Alzheimer\u2019s-like Tauopathy Mouse Model"],"prefix":"10.3390","volume":"13","author":[{"given":"Maciej","family":"Zadrozny","sequence":"first","affiliation":[{"name":"Mossakowski Medical Research Institute, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrycja","family":"Drapich","sequence":"additional","affiliation":[{"name":"Mossakowski Medical Research Institute, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Gasiorowska-Bien","sequence":"additional","affiliation":[{"name":"Mossakowski Medical Research Institute, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiktor","family":"Niewiadomski","sequence":"additional","affiliation":[{"name":"Mossakowski Medical Research Institute, 02-106 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2250-3920","authenticated-orcid":false,"given":"Charles R.","family":"Harrington","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK"},{"name":"TauRx Therapeutics Ltd., Aberdeen AB24 3FX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude M.","family":"Wischik","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK"},{"name":"TauRx Therapeutics Ltd., Aberdeen AB24 3FX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gernot","family":"Riedel","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3294-743X","authenticated-orcid":false,"given":"Grazyna","family":"Niewiadomska","sequence":"additional","affiliation":[{"name":"Mossakowski Medical Research Institute, 02-106 Warsaw, Poland"},{"name":"Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2212948","article-title":"Lecanemab in Early Alzheimer\u2019s Disease","volume":"388","author":"Swanson","year":"2023","journal-title":"N. 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