{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:32:24Z","timestamp":1789468344218,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Neuro-Bio Ltd."},{"DOI":"10.13039\/501100002924","name":"Fondo de Investigaciones Sanitarias","doi-asserted-by":"publisher","award":["PI17\/0026"],"award-info":[{"award-number":["PI17\/0026"]}],"id":[{"id":"10.13039\/501100002924","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fondo Europeo de Desarrollo Regional, FEDER \u2018Investing in your future\u2019"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Acetylcholinesterase (AChE) demonstrates non-enzymatic actions attributable to a 14mer bioactive peptide derived from its sixth exon, \u2018T14\u2019, a pivotal agent driving Alzheimer\u2019s disease (AD). Methods: To investigate this possible parallel between development and neurodegeneration, we tracked the expression and timeline of T14 in embryonic and neonatal rodent brain tissue in relation to the expression of its parent molecule, AChE, benchmarked against markers of neural maturation (NeuN) and neurodegenerative pathology (pTau) using sedimentation profiling, Western blotting, and qPCR. Results: We report two key findings: Firstly, while overall AChE activity, expression, and oligomeric assembly in the developing rodent cortex predominantly reflect AChE-T, endogenous T14 appear to selectively correspond with the AChE-R variant (r = 0.936, p = 0.0639), peaking at P7 before declining in tandem with NeuN and pTau. Secondly, application of exogenous peptide to cultured SHSY-5Y cells triggers the selective upregulation of this same variant, AChE-R (F(3,18) = 9.320, p &lt; 0.05). This effect is blocked by cotreatment with either mTORC1 inhibitor rapamycin or NBP14, an antagonist of T14. Conclusions: We conclude that in development, T14 and AChE-R are closely linked, that both are involved in a developmental mechanism most active in the embryonic brain, and that inappropriate reactivation of this mechanism in the mature brain could be the driver in the progression of AD.<\/jats:p>","DOI":"10.3390\/biom16091336","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T08:16:48Z","timestamp":1789460208000},"page":"1336","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Regulatory System in Brain Development and Death Driven by a Bioactive Peptide Linked to a Specific Isoform of Acetylcholinesterase"],"prefix":"10.3390","volume":"16","author":[{"given":"Adam Mohammed","family":"Khan","sequence":"first","affiliation":[{"name":"Neuro Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5140-9752","authenticated-orcid":false,"given":"Mar\u00eda-Salud","family":"Garc\u00eda-Ayll\u00f3n","sequence":"additional","affiliation":[{"name":"Unidad de Investigaci\u00f3n, Hospital General Universitario de Elche, FISABIO, 03203 Elche, Spain"},{"name":"Instituto de Neurociencias de Alicante, Universidad Miguel Hern\u00e1ndez-CSIC, 03550 San Juan de Alicante, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 03550 San Juan de Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen","family":"Hollings","sequence":"additional","affiliation":[{"name":"Neuro Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1848-4811","authenticated-orcid":false,"given":"Sara","family":"Garcia-Rat\u00e9s","sequence":"additional","affiliation":[{"name":"Neuro Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Greenfield","sequence":"additional","affiliation":[{"name":"Neuro Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/bies.950120904","article-title":"Cholinesterases preceding major tracts in vertebrate neurogenesis","volume":"12","author":"Layer","year":"1990","journal-title":"Bioessays"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1358\/dot.2003.39.1.740206","article-title":"The role of acetylcholinesterase in the pathogenesis of Alzheimer\u2019s disease","volume":"39","author":"Rees","year":"2003","journal-title":"Drugs Today"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/35067589","article-title":"Acetylcholinesterase--new roles for an old actor","volume":"2","author":"Soreq","year":"2001","journal-title":"Nat. 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