Manganese increases Aβ and Tau protein levels through proteasome 20S and heat shock proteins 90 and 70 alteration, leading to SN56 cholinergic cell death following single and repeated treatment

• Published in: Ecotoxicology and environmental safety Vol. 203; p. 110975
• Main Authors: Moyano, Paula, García, José Manuel, García, Jimena, Anadon, María José, Naval, María Victoria, Frejo, María Teresa, Sola, Emma, Pelayo, Adela, Pino, Javier del
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 15.10.2020
• Subjects: And pTau proteins; Heat shock proteins; Manganese; NRF2; P20S; SN56 basal forebrain cholinergic neurons; Mn; BF; DMSO; And pTau proteins; HO-1; MTT; GPX; HSPs; Aβ; BSA; DMEM; NRF2; FBS; ChAT; SN56 basal forebrain cholinergic neurons; UPS; P20S; PBS; AChE; HSF-1; SDS; Heat shock proteins; SOD1; NAC; Manganese
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2020.110975

Manganese (Mn) produces cholinergic neuronal loss in basal forebrain (BF) region that was related to cognitive dysfunction induced after single and repeated Mn treatment. All processes that generate cholinergic neuronal loss in BF remain to be understood. Mn exposure may produce the reduction of BF cholinergic neurons by increasing amyloid beta (Aβ) and phosphorylated Tau (pTau) protein levels, altering heat shock proteins’ (HSPs) expression, disrupting proteasome P20S activity and generating oxidative stress. These mechanisms, described to be altered by Mn in regions different than BF, could lead to the memory and learning process alteration produced after Mn exposure. The research performed shows that single and repeated Mn treatment of SN56 cholinergic neurons from BF induces P20S inhibition, increases Aβ and pTau protein levels, produces HSP90 and HSP70 proteins expression alteration, and oxidative stress generation, being the last two effects mediated by NRF2 pathway alteration. The increment of Aβ and pTau protein levels was mediated by HSPs and proteasome dysfunction. All these mechanisms mediated the cell decline observed after Mn treatment. Our results are relevant because they may assist to reveal the processes leading to the neurotoxicity and cognitive alterations observed after Mn exposure. [Display omitted] •Mn induces apoptotic cell death on SN56 basal forebrain cholinergic neurons.•Mn alter P20s activity by ROS and HSPs dysfunction.•Mn alter HSPs and antioxidant enzymes by NRF2 pathway alteration through KEAP1.•Mn induces cell death partially by oxidative stress generation and HSPs and proteasome dysfunction.