Protective Effects of Ambroxol on Aβ and α-Synuclein-Induced Neurotoxicity Through Glucocerebrosidase Activation in HT-22 Hippocampal Neuronal Cells DOI Open Access
Sheng‐Chieh Lin, Ching‐Chi Chang, Sing‐Hua Tsou

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(22), С. 12114 - 12114

Опубликована: Ноя. 12, 2024

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to neuronal death in DLB, particularly when exacerbated Aβ. Given role autophagy clearing misfolded proteins, exploring agents promote this pathway essential developing effective treatments. Ambroxol (AMBX), mucolytic drug, has demonstrated potential activating glucocerebrosidase (GCase), an enzyme enhances lysosomal function and facilitates autophagic clearance toxic protein aggregates, including αSyn. This study aims evaluate AMBX’s neuroprotective effects cellular model goal identifying new therapeutic target underlying pathology DLB. In study, HT-22 hippocampal cells were exposed Aβ, followed AMBX treatment. Our results showed significantly improved cell viability reduced apoptosis co-treated Additionally, restored GCase activity, promoted autophagy, oxidative stress, which turn mitigated aggregation phosphorylation. These findings suggest enhancing may help alleviate DLB-associated neurodegeneration. underscores as agent DLB supports further investigation animal models clinical trials validate its efficacy disease contexts.

Язык: Английский

Exploratory Analysis of the Association Between Plasma Ceramide Alterations and Cognitive Dysfunction in Parkinson's Disease DOI Creative Commons

Xu Liu,

Xuanjing Liu,

Yuning Liu

и другие.

CNS Neuroscience & Therapeutics, Год журнала: 2024, Номер 30(10)

Опубликована: Окт. 1, 2024

ABSTRACT Objective Prior research has underscored the importance of sphingolipid metabolism in Parkinson's disease (PD) pathogenesis. Our objective was to explore associations between plasma ceramide levels and PD patients with cognitive dysfunction (PD‐CD). Methods We enrolled two study populations from Eastern China Progression Markers Initiative (PPMI), comprising 290 (100 HCs, 160 PDs, 30 MSAs) 429 (125 HCs 304 PDs) participants, respectively. The ceramides (Cer 16:0, Cer 18:0, 24:0, 24:1) were tested via HPLC–MS/MS analysis. Results Compared those HC group, 24:1, 16:0/Cer 18:0/Cer 24:1/Cer 24:0 higher both MSA groups. Significant differences observed among PD‐NC (PD normal cognition), PD‐MCI mild impairment), PDD dementia) groups, group exhibiting highest levels. baseline (specifically, 24:0) demonstrated accelerated decline compared individuals who had lower during 5‐year follow‐up period. A biomarker panel including could effectively differentiate PD‐CD notable diagnostic accuracy. Conclusions results indicate that potentially be used as biomarkers for PD‐CD.

Язык: Английский

Процитировано

1
An improved Glucocerebrosidase Assay for Accurate Prediction of Lysosomal Dysfunction: Exemplified by Its Relevance in Parkinson’s Disease DOI

Aishwarya Babu,

Achanya S. Jayan,

Anjali Sethumadhavan

и другие.

Indian Journal of Clinical Biochemistry, Год журнала: 2024, Номер unknown

Опубликована: Май 20, 2024

Язык: Английский

Процитировано

0
AAV delivery of GBA1 suppresses alpha-synuclein accumulation in Parkinson's disease models and restores motor dysfunction in a Gaucher's disease model DOI Open Access
T. Okai, Sho Sato, Mugdha Deshpande

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 26, 2024

Abstract Biallelic mutations in the glucosylceramidase beta 1 ( GBA1 ) gene are underlying genetic cause of Gaucher’s disease (GD), resulting a deficient lysosomal hydrolase and subsequent accumulation glycosphingolipids. More recently, have been identified as most prevalent risk factor for Parkinson’s (PD), associated with more pronounced symptoms characterized by earlier onset accelerated cognitive decline. In these GBA-associated PD patients α-synuclein pathology is prominent, recent data suggest link between α-synucleinopathies mutations. Here, we explored effect supplementation on GD phenotypes using adeno-associated virus (AAV) system. We compared two AAV serotypes, AAV5 AAV9, different ubiquitous promoters, demonstrate that both promoters work efficiently albeit not same vitro vivo. overexpression reduces glucosylsphingosine (GlcSph) restores motor dysfunction mouse model. further can dissolve phospho-α-synuclein aggregation induced addition pre-formed fibril (PFF) primary neuron model suggesting direct β-Glucocerebrosidase (GCase) accumulation. vivo , show GCase inhibition induce insoluble high-molecular-weight delivery achieves robust reduction aggregates brain. summary, expression only GlcSph, but also removes which hallmark α-synucleinopathies. powerful approach to restore glucocerebrosidase function resolve misfolded protein, applications PD.

Язык: Английский

Процитировано

0
Protective Effects of Ambroxol on Aβ and α-Synuclein-Induced Neurotoxicity Through Glucocerebrosidase Activation in HT-22 Hippocampal Neuronal Cells DOI Open Access
Sheng‐Chieh Lin, Ching‐Chi Chang, Sing‐Hua Tsou

и другие.

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(22), С. 12114 - 12114

Опубликована: Ноя. 12, 2024

Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to neuronal death in DLB, particularly when exacerbated Aβ. Given role autophagy clearing misfolded proteins, exploring agents promote this pathway essential developing effective treatments. Ambroxol (AMBX), mucolytic drug, has demonstrated potential activating glucocerebrosidase (GCase), an enzyme enhances lysosomal function and facilitates autophagic clearance toxic protein aggregates, including αSyn. This study aims evaluate AMBX’s neuroprotective effects cellular model goal identifying new therapeutic target underlying pathology DLB. In study, HT-22 hippocampal cells were exposed Aβ, followed AMBX treatment. Our results showed significantly improved cell viability reduced apoptosis co-treated Additionally, restored GCase activity, promoted autophagy, oxidative stress, which turn mitigated aggregation phosphorylation. These findings suggest enhancing may help alleviate DLB-associated neurodegeneration. underscores as agent DLB supports further investigation animal models clinical trials validate its efficacy disease contexts.

Язык: Английский

Процитировано

0