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Current treatments are largely symptomatic, highlighting a critical need for disease-modifying therapies. Evidence suggests that \u03b1Syn aggregates contribute to neuronal death in DLB, particularly when exacerbated by A\u03b2. Given the role of autophagy in clearing misfolded proteins, exploring agents that promote this pathway is essential for developing effective treatments. Ambroxol (AMBX), a mucolytic drug, has demonstrated potential in activating glucocerebrosidase (GCase), an enzyme that enhances lysosomal function and facilitates the autophagic clearance of toxic protein aggregates, including \u03b1Syn. This study aims to evaluate AMBX\u2019s neuroprotective effects in a cellular model of DLB, with the goal of identifying new therapeutic agents that target the underlying pathology of DLB. In this study, HT-22 hippocampal neuronal cells were exposed to \u03b1Syn and A\u03b2, followed by AMBX treatment. Our results showed that AMBX significantly improved cell viability and reduced apoptosis in cells co-treated with \u03b1Syn and A\u03b2. Additionally, AMBX restored GCase activity, promoted autophagy, and reduced oxidative stress, which in turn mitigated \u03b1Syn aggregation and phosphorylation. These findings suggest that by activating GCase and enhancing autophagy, AMBX may help alleviate DLB-associated neurodegeneration. This study underscores the potential of AMBX as a therapeutic agent for DLB and supports further investigation in animal models and clinical trials to validate its efficacy in neurodegenerative disease contexts.<\/jats:p>","DOI":"10.3390\/ijms252212114","type":"journal-article","created":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T05:21:59Z","timestamp":1731388919000},"page":"12114","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Protective Effects of Ambroxol on A\u03b2 and \u03b1-Synuclein-Induced Neurotoxicity Through Glucocerebrosidase Activation in HT-22 Hippocampal Neuronal Cells"],"prefix":"10.3390","volume":"25","author":[{"given":"Sheng-Chieh","family":"Lin","sequence":"first","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Chi","family":"Chang","sequence":"additional","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Psychiatry, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7574-028X","authenticated-orcid":false,"given":"Sing-Hua","family":"Tsou","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2552-4516","authenticated-orcid":false,"given":"Pai-Yi","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Show Chwan Memorial Hospital, Changhua 500, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju-Fang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Changhua Christian Hospital, Changhua 500, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0180-1822","authenticated-orcid":false,"given":"Hui-Chih","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3729-989X","authenticated-orcid":false,"given":"Wei-Jen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Chung Shan Medical University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Jui","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Psychology, Chung Shan Medical University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4553-3727","authenticated-orcid":false,"given":"Chih-Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan"},{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101441","DOI":"10.1016\/j.disamonth.2022.101441","article-title":"Recent advances in Lewy body dementia: A comprehensive review","volume":"69","author":"Prasad","year":"2023","journal-title":"Dis. 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