{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:00:25Z","timestamp":1787317225159,"version":"build-2736575974"},"reference-count":74,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2019s Horizon 2020 research and innovation programme","award":["101037509"],"award-info":[{"award-number":["101037509"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["NeuroSci"],"abstract":"<jats:p>Per- and polyfluoroalkyl substances are persistent environmental contaminants increasingly implicated in neurotoxicity. Establishing causality and mechanisms relevant to Alzheimer\u2019s disease, Parkinson\u2019s disease, and multiple sclerosis requires human-relevant systems that capture exposure, barrier function, and brain circuitry. We review advanced cellular platforms\u2014iPSC-derived neuronal and glial cultures, cerebral and midbrain organoids, and chip-based microphysiological systems\u2014that model disease-relevant phenotypes (A\u03b2\/tau pathology, dopaminergic vulnerability, myelination defects) under controlled PFAS exposures and defined genetic risk backgrounds. Modular, fluidically coupled BBB-on-chip \u2192 brain-organoid microphysiological systems have been reported, enabling chronic, low-dose PFAS perfusion under physiological shear, real-time barrier integrity readouts such as transepithelial\/transendothelial electrical resistance (TEER), quantification of PFAS partitioning and translocation, and downstream neuronal\u2013glial responses assessed by electrophysiology and multi-omics. Across platforms, convergent PFAS-responsive processes emerge\u2014mitochondrial dysfunction and oxidative stress, lipid\/ceramide dysregulation, neuroinflammatory signaling, and synaptic\/network impairments\u2014providing a mechanistic scaffold for biomarker discovery and gene\u2013environment interrogation with isogenic lines. We outline principles for exposure design (environmentally relevant ranges, longitudinal paradigms), multimodal endpoints (omics, electrophysiology, imaging), and cross-lab standardization to improve comparability. Together, these models advance the quantitative evaluation of PFAS neurotoxicity and support translation into risk assessment and therapeutic strategies.<\/jats:p>","DOI":"10.3390\/neurosci6040125","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T14:52:24Z","timestamp":1765205544000},"page":"125","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Advanced Cellular Models for Neurodegenerative Diseases and PFAS-Related Environmental Risks"],"prefix":"10.3390","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5605-8968","authenticated-orcid":false,"given":"Davide","family":"Rotondo","sequence":"first","affiliation":[{"name":"Department of Science and Technological Innovation, Universit\u00e0 del Piemonte Orientale, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-3720","authenticated-orcid":false,"given":"Laura","family":"Lagostena","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, National Research Council, Via de Marini 6, 16149 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0247-9372","authenticated-orcid":false,"given":"Valeria","family":"Magnelli","sequence":"additional","affiliation":[{"name":"Department of Science and Technological Innovation, Universit\u00e0 del Piemonte Orientale, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7945-3712","authenticated-orcid":false,"given":"Francesco","family":"Dondero","sequence":"additional","affiliation":[{"name":"Department of Science and Technological Innovation, Universit\u00e0 del Piemonte Orientale, 15121 Alessandria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1093\/toxsci\/kfm128","article-title":"Perfluoroalkyl Acids: A review of monitoring and toxicological findings","volume":"99","author":"Lau","year":"2007","journal-title":"Toxicol. 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