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Cholinergic loss represents a central pathological hallmark of AD; however, the underlying molecular mechanisms remain incompletely understood. Although various in-vitro models are available, many are limited by species-specific differences, high cost, and technical complexity. Human neuroblastoma (SH-SY5Y) cells can be differentiated into neuron-like cells and represent a practical alternative for AD research. This study aimed to optimise retinoic acid (RA)-based differentiation conditions to enhance cholinergic characteristics in SH-SY5Y cells and evaluate their susceptibility to AD-related stressors as a simplified, cost-effective model for preliminary high-throughput AD studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A structured literature search (2000\u20132025) was conducted using PubMed and ScienceDirect. After screening based on predefined criteria, 23 relevant studies were analysed for differentiation inducers, serum concentration, duration, neuronal markers, and cholinergic markers. Here, a simplified RA-only protocol was evaluated using 10\u00b5M RA with 1% or 3% heat-inactivated foetal bovine serum (1% or 3% HI-FBS) over 3, 5, and 7 days. Neuronal differentiation was assessed by morphological analysis, neurite length measurement, choline acetyltransferase (\n                      <jats:italic>ChAT<\/jats:italic>\n                      ) and acetylcholinesterase (\n                      <jats:italic>AChE<\/jats:italic>\n                      ) gene expressions, acetylcholinesterase (AChE) activity. Additionally, model relevance was further evaluated using AD-associated stressors such as streptozotocin (STZ), hydrogen peroxide (H\u2082O\u2082), lipopolysaccharide (LPS), and aluminium chloride (AlCl\u2083).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Although most protocols generated mature neuron-like cells, only\u2009~\u200930% reported cholinergic marker expression, with retinoic acid (RA) and brain-derived neurotrophic factor (BDNF) as the most common inducers. This study reports that differentiation with 1% HI-FBS with 10\u00b5M RA for 7 days produced pronounced neuronal morphology, significant neurite extension, and extensive branching. These cells demonstrated a cholinergic-like phenotype, with significant upregulation of\n                      <jats:italic>ChAT<\/jats:italic>\n                      and\n                      <jats:italic>AChE<\/jats:italic>\n                      gene expressions, accompanied by increased AChE enzymatic activity. These neuron-like cells also showed dose-dependent responses to STZ, H\u2082O\u2082, and AlCl\u2083, with time-dependent effects observed for H\u2082O\u2082 and AlCl\u2083. Notably, cells were resistant to LPS-induced cytotoxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings support the utility of this RA-differentiated SH-SY5Y for neuronal-like cells for cholinergic-like model (1% HI-FBS, 10\u00b5M RA) as a practical and cost-effective platform for high-throughput AD drug screening.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11033-026-12156-4","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T12:51:47Z","timestamp":1782219107000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["In-vitro modelling of Alzheimer\u2019s disease using cholinergic neurons derived from human neuroblastoma (SH-SY5Y) retinoic acid-induced differentiation"],"prefix":"10.1007","volume":"53","author":[{"given":"Muhammad-Safuan","family":"Zainuddin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasthuri","family":"Bai Magalingam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narendra","family":"Pamidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adzzie Shazleen","family":"Azman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3889-0163","authenticated-orcid":false,"given":"Saatheeyavaane","family":"Bhuvanendran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"issue":"18","key":"12156_CR1","doi-asserted-by":"publisher","first-page":"13900","DOI":"10.3390\/ijms241813900","volume":"24","author":"FR Buccellato","year":"2023","unstructured":"Buccellato FR, D\u2019Anca M, Tartaglia GM, Del Fabbro M, Scarpini E, Galimberti D (2023) Treatment of Alzheimer\u2019s Disease: Beyond Symptomatic Therapies. 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