Compound C enhances tau phosphorylation at Serine396 via PI3K activation in an AMPK and rapamycin independent way in differentiated SH-SY5Y cells

Shohreh Majd, Simon Koblar, John Power

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Aggregation of hyperphosphorylated tau (p-tau) in the form of neurofibrillary tangles (NFT) is a main hallmark for Alzheimer's disease (AD). Activation of cellular metabolic axis, made of adenosine monophosphate kinase protein kinase (AMPK) and mammalian target of rapamycin (mTOR) have been implicated in generating tau pathology of AD. Thus, blocking either of these two proteins or both, are suggested as the future therapeutic approaches for AD. How and to what level these approaches could be applied, however are not entirely clear. By using Compound C (CC) in this study, we showed a substantial decrease in mTOR activity in a rapamycin-independent way without blocking AMPK. This decline in mTOR activity was accompanied by an increase in phosphoinositide 3 kinase (PI3K)/Akt activity and a parallel increase in p-tau (Ser396) but not p-tau (Ser262) in differentiated SH-SY5Y neuroblastoma cells. This elevation was blocked when the cells were treated with 15 μM of LY294002, a specific PI3K inhibitor, suggesting PI3K involvement in CC-mediated tau hyperphosphorylation at Ser396. For all groups the activity levels of glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase-5 (cdk5) and protein phosphatase 2A (PP2A), the other main kinases and phosphatase responsible for tau phosphorylation/dephosphorylation remained unchanged. Collectively, our results demonstrate that rapamycin-independent blocking of mTOR enhances p-tau (Ser396) in a PI3K-dependent way, suggesting the careful consideration of future therapeutic approaches for AD, which will be based on mTOR inhibition.

Original languageEnglish
Pages (from-to)53-61
Number of pages9
JournalNeuroscience Letters
Volume670
DOIs
Publication statusPublished - 23 Mar 2018

Keywords

  • Adenosine monophosphate kinase protein kinase
  • Akt
  • Compound C
  • Mammalian target of rapamycin
  • Phosphoinositide 3 kinase
  • Rapamycin
  • Tau (Ser) phosphorylation

ASJC Scopus subject areas

  • Neuroscience(all)

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