{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T15:41:41Z","timestamp":1785512501715,"version":"3.56.0"},"reference-count":359,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre","doi-asserted-by":"publisher","award":["2022\/47\/O\/NZ7\/00155"],"award-info":[{"award-number":["2022\/47\/O\/NZ7\/00155"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Neurodegenerative diseases (NDDs), including Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002\u20132012) estimated ~99.6% attrition, while PD programs (1999\u20132019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons\/glia, neuron\u2013glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood\u2013brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune\/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK\/PD-driven development for brain-directed degraders.<\/jats:p>","DOI":"10.3390\/molecules31020320","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T09:57:02Z","timestamp":1768816622000},"page":"320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Experimental Models and Translational Strategies in Neuroprotective Drug Development with Emphasis on Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1724-0089","authenticated-orcid":false,"given":"Przemys\u0142aw","family":"Nizi\u0144ski","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Chair of Pharmacology and Biology, Faculty of Health Sciences, Medical University of Lublin, 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4657-490X","authenticated-orcid":false,"given":"Karolina","family":"Szalast","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Chair of Pharmacology and Biology, Faculty of Health Sciences, Medical University of Lublin, 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8082-535X","authenticated-orcid":false,"given":"Anna","family":"Makuch-Kocka","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Chair of Pharmacology and Biology, Faculty of Health Sciences, Medical University of Lublin, 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2090-1300","authenticated-orcid":false,"given":"Kinga","family":"Paruch-Nosek","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Chair of Pharmacology and Biology, Faculty of Health Sciences, Medical University of Lublin, 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Ciechanowska","sequence":"additional","affiliation":[{"name":"Department of Integrated Medical Care, Faculty of Medicine, Collegium Medicum, The Mazovian Academy in P\u0142ock, 09-402 P\u0142ock, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Plech","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Chair of Pharmacology and Biology, Faculty of Health Sciences, Medical University of Lublin, 20-080 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s40035-017-0096-2","article-title":"Disease Modification and Neuroprotection in Neurodegenerative Disorders","volume":"6","author":"Cummings","year":"2017","journal-title":"Transl. 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