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In an in vitro AD model, this study aimed to comparatively assess the neuroprotective effects of the citrus flavonoid Hesperidin and the casein kinase 2 (CK2) inhibitor 5,6-dichloro-1-\u03b2-D-ribofuranosyl benzimidazole (DRB) as potential therapeutic targets for AD. First, SH-SY5Y neuroblastoma cells were differentiated into cholinergic neuron-like cells using all<jats:italic>-trans<\/jats:italic> retinoic acid (RA) and brain-derived neurotrophic factor (BDNF). Then, to generate an in vitro AD model, 20\u00a0\u03bcM A\u03b2<jats:sub>1\u201342<\/jats:sub> was applied to induce neurotoxicity in differentiated SH-SY5Y cells. The neuroprotective effects of the CK2 inhibitor DRB and Hesperidin on the in vitro AD model were evaluated using MTT, RT-qPCR, and ELISA methods. Both Hesperidin and DRB, at high concentrations, reduced cell viability in differentiated SH-SY5Y cells for 24 and 48\u00a0h (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05 to <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Pre-treatment with Hesperidin at 25 and 50\u00a0\u00b5M and DRB at 0.25 and 0.5\u00a0\u00b5M for 24\u00a0h increased ADAM10 gene expression and decreased BACE1 gene expression, both of which are associated with AD markers, compared to the 20\u00a0\u00b5M A\u03b2<jats:sub>1-42<\/jats:sub> treatment group (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Pre-treatment with the DRB at 0.25 and 0.5\u00a0\u00b5M concentrations for 24\u00a0h decreased CK2\u03b1 gene expression in the in vitro AD model compared to the 20\u00a0\u00b5M A\u03b2<jats:sub>1-42<\/jats:sub> treatment group (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), whereas Hesperidin had no effect (<jats:italic>p<\/jats:italic>\u2009&gt;\u20090.05). Both pre-treatment with Hesperidin and DRB significantly decreased A\u03b2<jats:sub>1-42<\/jats:sub> levels (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), p-Tau (T181) levels (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), and the Bax\/Bcl-2 ratio (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). As a result, our study showed that both Hesperidin and DRB inhibited A\u03b2 production by suppressing the amyloidogenic pathway and activating the non-amyloidogenic pathway while also exerting an inhibitory effect on neuronal apoptosis. CK2 may be a potential therapeutic target and could contribute to the pathophysiology of AD. However, these findings should be validated by further studies.<\/jats:p>","DOI":"10.1007\/s12035-025-05082-2","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:09:18Z","timestamp":1748563758000},"page":"12722-12735","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Neuroprotective Effects of Hesperidin and CK2 Inhibitor DRB on A\u03b21-42-Induced Neurotoxicity in Differentiated SH-SY5Y Cells"],"prefix":"10.1007","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3555-3946","authenticated-orcid":false,"given":"Hamiyet","family":"Eciroglu-Sarban","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8429-009X","authenticated-orcid":false,"given":"Pinar","family":"Altin-Celik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1661-0631","authenticated-orcid":false,"given":"Pelin","family":"Kelicen-Ugur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6473-5813","authenticated-orcid":false,"given":"Hamiyet","family":"Donmez-Altuntas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"issue":"24","key":"5082_CR1","doi-asserted-by":"publisher","first-page":"5789","DOI":"10.3390\/molecules25245789","volume":"25","author":"Z Breijyeh","year":"2020","unstructured":"Breijyeh Z, Karaman R, Mu\u00f1oz-Torrero D, Dembinski R (2020) Comprehensive Review on Alzheimer\u2019s Disease: Causes and Treatment. 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