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The vast majority of AD is late onset (LOAD) without a specific genetic cause, although many genetic and non-genetic risk factors have been identified. One of the most significant modifiable risk factors is diet\/lifestyle, with type-2 diabetes mellitus (T2DM) increasing LOAD risk by over 50%. Despite the epidemiological data, the reasons for this link are not understood. Here, we investigated whether altered free fatty acid (FFA) levels seen in T2DM can adversely affect neuronal differentiation, a crucial stage in adult hippocampal neurogenesis (AHN), which is defective in LOAD. We show that chronic exposure of the neuroblastoma cell line, SH-SY5Y to T2DM-relevant levels of the FFAs, oleate and palmitate, profoundly affects the differentiation of these cells. This effect is particularly pronounced for the saturated FFA, palmitate, resulting in neuronal cells of altered morphology, lacking expression of key synaptic markers. We further demonstrate that this exposure dysregulates insulin signalling, GSK3\u03b2 activity, CDK5 levels and CREB phosphorylation. Crucially, these effects were only observed on exposure during differentiation and can be partially replicated in hiPSC-derived forebrain neurones. Although APP expression is increased by palmitate exposure, there was no increase in secreted or intracellular A\u03b2, and tau phosphorylation was reduced, implying that these defects are separate from the classical hallmarks of AD. We conclude that long-term, chronic exposure of differentiating neurones induces pathological changes that may explain the link between T2DM and LOAD.<\/jats:p>","DOI":"10.1007\/s12035-025-05367-6","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T01:32:31Z","timestamp":1764207151000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Chronic Fatty Acid Exposure Disrupts SH-SY5Y and Neuronal Differentiation and Is a Potential Link Between Type-2 Diabetes and Alzheimer\u2019s Disease"],"prefix":"10.1007","volume":"63","author":[{"given":"Imogen L.","family":"Targett","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate","family":"Pring","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana I. 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