Advertisement

Cubeben induces autophagy via PI3K-AKT-mTOR pathway to protect primary neurons against amyloid beta in Alzheimer’s disease

  • Xiangqing Li
  • Jinqiu Song
  • Ruijian DongEmail author
Article
  • 60 Downloads

Abstract

Autophagy is a lysosomal degradative process by which it recycles cytosolic components and degrades protein aggregates inside cells. Here, we identified cubeben as an inducer of autophagy in primary neuronal cells. Autophagy induction was accompanied the upregulation of autophagic proteins like Beclin, ATG5, ATG12 and lipidation of LC3-II in primary neuronal cells. Cubeben induces autophagy by the inhibition of PI3K-AKT pathway in a dose dependent manner. Constitutive active P110α abrogates cubeben induced autophagic induction in primary neuronal cells. Furthermore, cubeben inhibits amyloid beta induced toxicity in primary neuronal cells. Thus our data suggests that cubeben as a potential anti-Alzheimer therapeutic lead.

Keywords

Autophagy Alzheimer’s disease Amyloid beta Primary neuronal cells Neuroprotection 

Notes

Funding

Financial assistance was provided by National Natural Science Foundation of China under Grant No. 2018JM001689.

References

  1. Abramov AY, Canevari L, Duchen MR (2004) β-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575CrossRefGoogle Scholar
  2. Baranello J, Robert Bharani KL, Padmaraju V, Chopra N, Lahiri DK, Greig NH, Pappolla MA, Sambamurti K (2015) Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer’s disease. Curr Alzheimer Res 12:32–46CrossRefGoogle Scholar
  3. Barbero-Camps E, Roca-Agujetas V, Bartolessis I, de Dios C, Fernández-Checa JC, Marí M, Morales A, Hartmann T, Colell A (2018) Cholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion. Autophagy 14:1129–1154CrossRefGoogle Scholar
  4. Benito-Cuesta I, Diez H, Ordoñez L, Wandosell F (2017) Assessment of autophagy in neurons and brain tissue. Cells 6:25CrossRefGoogle Scholar
  5. Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH, Nixon RA (2008) Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci 28:6926–6937CrossRefGoogle Scholar
  6. Cai Z, Yan L-J (2013) Rapamycin, autophagy, and Alzheimer’s disease. J Biochem Pharmacol Res 1:84Google Scholar
  7. Eskelinen E-L (2005) Maturation of autophagic vacuoles in mammalian cells. Autophagy 1:1–10CrossRefGoogle Scholar
  8. Eskelinen E-L, Saftig P (2009) Autophagy: a lysosomal degradation pathway with a central role in health and disease. Biochim Biophys Acta (BBA) Mol Cell Res 1793:664–673CrossRefGoogle Scholar
  9. Funderburk SF, Marcellino BK, Yue Z (2010) Cell “self-eating”(autophagy) mechanism in Alzheimer's disease. Mt Sinai J Med J Transl Pers Med 77:59–68CrossRefGoogle Scholar
  10. Huang H-C, Jiang Z-F (2009) Accumulated amyloid-β peptide and hyperphosphorylated tau protein: relationship and links in Alzheimer's disease. J Alzheimer's Dis 16:15–27CrossRefGoogle Scholar
  11. Johnson IP (2015) Age-related neurodegenerative disease research needs aging models. Front Aging Neurosci 7:168CrossRefGoogle Scholar
  12. Jung CH, Ro S-H, Cao J, Otto NM, Kim D-H (2010) mTOR regulation of autophagy. FEBS Lett 584:1287–1295CrossRefGoogle Scholar
  13. Kingsley K, Plopper GE (2005) Platelet-derived growth factor modulates rat vascular smooth muscle cell responses on laminin-5 via mitogen-activated protein kinase-sensitive pathways. Cell Commun Signal 3:2CrossRefGoogle Scholar
  14. Marchi N, Banjara M, Janigro D (2016) Blood–brain barrier, bulk flow, and interstitial clearance in epilepsy. J Neurosci Methods 260:118–124CrossRefGoogle Scholar
  15. Nah J, Yuan J, Jung Y-K (2015) Autophagy in neurodegenerative diseases: from mechanism to therapeutic approach. Mol Cells 38:381CrossRefGoogle Scholar
  16. Nilsson P (2014) Saido TC (2014) Dual roles for autophagy: degradation and secretion of Alzheimer's disease Aβ peptide. Bioessays 36:570–578CrossRefGoogle Scholar
  17. Park H-S, Quan KT, Han J-H, Jung S-H, Lee D-H, Jo E, Lim T-W, Heo K-S, Na MK, Myung C-S (2017) Rubiarbonone C inhibits platelet-derived growth factor-induced proliferation and migration of vascular smooth muscle cells through the focal adhesion kinase, MAPK and STAT3 Tyr705 signalling pathways. Br J Pharmacol 174:4140–4154CrossRefGoogle Scholar
  18. Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S et al (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice. J Clin Investig 118:2190–2199Google Scholar
  19. Richardson A, Galvan V, Lin A-L, Oddo S (2015) How longevity research can lead to therapies for Alzheimer's disease: the rapamycin story. Exp Gerontol 68:51–58CrossRefGoogle Scholar
  20. Shimizu S (2018) Association between autophagy and neurodegenerative diseases. Front Neurosci 12:255Google Scholar
  21. Yue Z, Friedman L, Komatsu M, Tanaka K (2009) The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases. Biochim Biophys Acta (BBA) Mol Cell Res 1793:1496–1507CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of NeurologyZiBo Central HospitalZiboChina

Personalised recommendations