Early effects of aluminum chloride on beta-secretase mRNA expression in a neuronal model of beta-amyloid toxicity.
Amyloid beta peptide (Abeta), generated by proteolytic cleavage of the amyloid precursor protein (APP), plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). The key step in the generation of Abeta is cleavage of APP by beta-secretases (beta-site APP-cleaving enzyme 1 (BACE1) and BACE2). There has been suggestion of interaction between aluminum and several AD-associated pathways. However, the underlying mechanisms still remain unclear. Here, we report the effects of aluminum chloride (AlCl(3)) in Abeta-induced toxicity using differentiated neuronal SH-SY5Y cells. The metal significantly enhances Abeta-induced cell death at concentrations ranging from 50 to 300 microM after 24 and 48 h. After 72 and 96 h treatment, cell death is increased already at 10 microM. Early coexposure of cells to 10 microM AlCl(3) and 2 microM Abeta differentially affected beta-secretase mRNA levels as compared to single Abeta treatment after 1 and 3 h. BACE1 levels were slightly reduced after 1 h and significantly increased after 3 h exposure, whereas BACE2 levels were increased at both times considered. Both genes' mRNA levels were downregulated at longer times (6, 12, and 24 h). Although these results indicate that aluminum toxicity is correlated to changes in both BACE1 and BACE2 expression levels, the subsequent common downregulation observed suggests that aluminum involvement in the Abeta cascade is subtle, and other underlying mechanisms might be involved.
Castorina
Alessandro
A
Department of Anatomy, Diagnostic Pathology, Legal Medicine, Hygiene and Public Health, University of Catania, Catania, Italy.
Tiralongo
Adriana
A
Giunta
Salvatore
S
Carnazza
Maria Luisa
ML
Scapagnini
Giovanni
G
D'Agata
Velia
V
D000077410:Aluminum Chloride; D017607:Aluminum Compounds / Q000633:toxicity*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D017607:Aluminum Compounds; D016229:Amyloid beta-Peptides; D002712:Chlorides; D012333:RNA, Messenger; D000077410:Aluminum Chloride; D053829:Amyloid Precursor Protein Secretases