Protective Effects of Ambroxol on Aβ and α-Synuclein-Induced Neurotoxicity Through Glucocerebrosidase Activation in HT-22 Hippocampal Neuronal Cells.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Glucosylceramidase*/metabolism ; alpha-Synuclein*/metabolism ; Ambroxol*/pharmacology ; Neurons*/drug effects ; Neurons*/metabolism ; Amyloid beta-Peptides*/metabolism ; Amyloid beta-Peptides*/toxicity ; Hippocampus*/drug effects ; Hippocampus*/metabolism ; Neuroprotective Agents*/pharmacology ; Autophagy*/drug effects; Animals ; Mice ; Cell Line ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Cell Survival/drug effects ; Humans ; Lewy Body Disease/drug therapy ; Lewy Body Disease/metabolism ; Lewy Body Disease/pathology

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing with amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting a critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to neuronal death in DLB, particularly when exacerbated by Aβ. 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 αSyn. This study aims to evaluate AMBX's 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 αSyn and Aβ, followed by AMBX treatment. Our results showed that AMBX significantly improved cell viability and reduced apoptosis in cells co-treated with αSyn and Aβ. Additionally, AMBX restored GCase activity, promoted autophagy, and reduced oxidative stress, which in turn mitigated αSyn 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.

Ann Neurol. 2016 Nov;80(5):766-775. (PMID: 27859541)
Cell Biosci. 2021 Nov 19;11(1):196. (PMID: 34798911)
Mol Neurobiol. 2022 Sep;59(9):5379-5407. (PMID: 35699874)
Rev Neurosci. 2013;24(2):115-23. (PMID: 23314528)
Int J Mol Sci. 2023 Jun 17;24(12):. (PMID: 37373401)
Hum Mol Genet. 2016 Aug 15;25(16):3432-3445. (PMID: 27378698)
Alzheimers Res Ther. 2014 Oct 27;6(5):73. (PMID: 25580161)
Int J Mol Sci. 2024 Feb 01;25(3):. (PMID: 38339074)
Int J Mol Sci. 2024 Aug 24;25(17):. (PMID: 39273146)
Exp Neurol. 2016 Jan;275 Pt 1:84-98. (PMID: 26515689)
Neurochem Int. 2024 Sep;178:105774. (PMID: 38797393)
Parkinsonism Relat Disord. 2021 Mar;84:112-121. (PMID: 33609962)
Alzheimers Res Ther. 2014 Jul 21;6(4):46. (PMID: 25484925)
Front Comput Neurosci. 2023 Apr 13;17:1068150. (PMID: 37122994)
NPJ Parkinsons Dis. 2023 May 11;9(1):74. (PMID: 37169750)
Neural Regen Res. 2024 Nov 1;19(11):2345-2346. (PMID: 38526267)
CNS Neurosci Ther. 2018 Jan;24(1):47-57. (PMID: 29092095)
Mol Neurodegener. 2024 Aug 6;19(1):60. (PMID: 39107789)
J Am Chem Soc. 2023 Aug 23;145(33):18276-18285. (PMID: 37556728)
Antioxidants (Basel). 2021 Apr 28;10(5):. (PMID: 33924878)
J Neuropathol Exp Neurol. 2013 Dec;72(12):1203-12. (PMID: 24226269)
Dis Mon. 2023 May;69(5):101441. (PMID: 35690493)
Mol Neurodegener. 2021 Sep 9;16(1):63. (PMID: 34503546)
Cells. 2024 Jan 25;13(3):. (PMID: 38334615)
Mol Genet Metab. 2024 Sep-Oct;143(1-2):108556. (PMID: 39116528)
Brain Commun. 2023 Mar 29;5(2):fcad099. (PMID: 37065090)
Eur J Pharmacol. 2020 Oct 5;884:173446. (PMID: 32739173)
Acta Neuropathol Commun. 2024 Feb 15;12(1):28. (PMID: 38360761)
Neural Regen Res. 2017 Mar;12(3):380-384. (PMID: 28469644)
Mol Genet Metab Rep. 2020 Dec 09;25:100667. (PMID: 33335836)

CSH-2021-C-009 Chung Shan Medical University Hospital; 112-2320-B-040-003-MY3 and 111-2320-B-040-017-MY3 National Science and Technology Council; NCHU-CSMU-11105 National Chung Hsing University and Chung Shan Medical University

Keywords: Ambroxol (AMBX); amyloid β (Aβ); autophagy; glucocerebrosidase; αSyn (αSyn)

EC 3.2.1.45 (Glucosylceramidase)
0 (alpha-Synuclein)
200168S0CL (Ambroxol)
0 (Amyloid beta-Peptides)
0 (Neuroprotective Agents)

Date Created: 20241127 Date Completed: 20241127 Latest Revision: 20241130

20241202

PMC11593818

10.3390/ijms252212114

39596182