{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T08:28:52Z","timestamp":1786609732225,"version":"build-2736575974"},"reference-count":142,"publisher":"Portland Press Ltd.","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Alzheimer's Research UK","award":["ARUK-TERM3DDI-OX"],"award-info":[{"award-number":["ARUK-TERM3DDI-OX"]}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Alzheimer\u2019s disease (AD) is a complex neurodegenerative disorder involving amyloid-\u03b2 deposition, tau aggregation, neuroinflammation, synaptic dysfunction, and microvascular and epigenetic changes. Although recent therapeutic developments have energised the field, effective and widely accessible disease-modifying treatments remain limited. This reflects both the biological complexity of AD and the continuing challenge of validating drug targets in the central nervous system (CNS).<\/jats:p>\n                  <jats:p>Chemical probes are small molecules designed to investigate the function of specific proteins in biological systems. When selected and used carefully, they provide powerful tools for testing how particular targets and pathways contribute to AD biology. High-quality chemical probes for AD targets must have high selectivity, confirmed target engagement, and CNS exposure adequate for the specific biological question, with low efflux, and biomarker evidence that the intended target is engaged in brain-relevant tissue. CNS penetration should be interpreted alongside mechanism-appropriate pharmacodynamic biomarkers, since cerebrospinal fluid measurements and modelled Kp,uu do not always directly reflect brain exposure.<\/jats:p>\n                  <jats:p>Chemical probes have shaped current understanding of major AD-relevant pathways, including amyloid precursor protein processing by BACE1 and \u03b3-secretase, tau phosphorylation and aggregation, epigenetic regulation, and neuroinflammatory signalling. Several compounds initially developed as potential therapies have provided valuable mechanistic insight, even where they did not translate into clinical benefit.<\/jats:p>\n                  <jats:p>New modalities, including targeted protein degradation, molecular glues, and peptides, are expanding the range of AD biology that can be studied. These developments illustrate the value and limitations of chemical probes and underline the need for rigorous probe selection, validation, and experimental design in AD research.<\/jats:p>","DOI":"10.1042\/ebc20260014","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T07:47:47Z","timestamp":1786607267000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chemical probes for Alzheimer\u2019s disease targets"],"prefix":"10.1042","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9335-4411","authenticated-orcid":false,"given":"Sheenagh\u00a0G.","family":"Aiken","sequence":"first","affiliation":[{"name":"University of Oxford Centre for Medicines Discovery, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7323-8587","authenticated-orcid":false,"given":"Tryfon","family":"Zarganes-Tzitzikas","sequence":"additional","affiliation":[{"name":"University of Oxford Centre for Medicines Discovery, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8950-7646","authenticated-orcid":false,"given":"Paul\u00a0E.","family":"Brennan","sequence":"additional","affiliation":[{"name":"University of Oxford Centre for Medicines Discovery, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"2026081303474340000_B1","doi-asserted-by":"publisher","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"key":"2026081303474340000_B2","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/s41582-021-00520-w","article-title":"Developing the ATX(N) classification for use across the Alzheimer disease continuum","volume":"17","author":"Hampel","year":"2021","journal-title":"Nat. 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