Influence of metabolic stress and metformin on synaptic protein profile in SH-SY5Y-derived neurons.

Autor: Yang AJT; Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St Catharines, Ontario, Canada., Mohammad A; Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St Catharines, Ontario, Canada., Finch MS; Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St Catharines, Ontario, Canada., Tsiani E; Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St Catharines, Ontario, Canada., Spencer G; Department of Biological Sciences, Brock University, St Catharines, Ontario, Canada.; Centre for Neuroscience, Brock University, St. Catharines, Ontario, Canada., Necakov A; Department of Biological Sciences, Brock University, St Catharines, Ontario, Canada.; Centre for Neuroscience, Brock University, St. Catharines, Ontario, Canada., MacPherson REK; Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St Catharines, Ontario, Canada.; Centre for Neuroscience, Brock University, St. Catharines, Ontario, Canada.
Jazyk: angličtina
Zdroj: Physiological reports [Physiol Rep] 2023 Nov; Vol. 11 (22).
DOI: 10.14814/phy2.15852
Abstrakt: Insulin resistance (IR) is associated with reductions in neuronal proteins often observed with Alzheimer's disease (AD), however, the mechanisms through which IR promotes neurodegeneration/AD pathogenesis are poorly understood. Metformin (MET), a potent activator of the metabolic regulator AMPK is used to treat IR but its effectiveness for AD is unclear. We have previously shown that chronic AMPK activation impairs neurite growth and protein synthesis in SH-SY5Y neurons, however, AMPK activation in IR was not explored. Therefore, we examined the effects of MET-driven AMPK activation with and without IR. Retinoic acid-differentiated SH-SY5Y neurons were treated with: (1) Ctl: 24 h vehicle followed by 24 h Vehicle; (2) HI: 100 nM insulin (24 h HI followed by 24 h HI); or (3) MET: 24 h vehicle followed by 24 h 2 mM metformin; (4) HI/MET: 24 h 100 nM insulin followed by 24 h 100 nM INS+2 mM MET. INS and INS/MET groups saw impairments in markers of insulin signaling (Akt S473, mTOR S2448, p70s6k T389, and IRS-1S636) demonstrating IR was not recovered with MET treatment. All treatment groups showed reductions in neuronal markers (post-synaptic marker HOMER1 mRNA content and synapse marker synaptophysin protein content). INS and MET treatments showed a reduction in the content of the mature neuronal marker NeuN that was prevented by INS/MET. Similarly, increases in cell size/area, neurite length/area observed with INS and MET, were prevented with INS/MET. These findings indicate that IR and MET impair neuronal markers through distinct pathways and suggest that MET is ineffective in treating IR-driven impairments in neurons.
(© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
Databáze: MEDLINE
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