Molecular Neurobiology

, Volume 54, Issue 8, pp 5815–5828 | Cite as

Neuroprotection Through Rapamycin-Induced Activation of Autophagy and PI3K/Akt1/mTOR/CREB Signaling Against Amyloid-β-Induced Oxidative Stress, Synaptic/Neurotransmission Dysfunction, and Neurodegeneration in Adult Rats

  • Abhishek Kumar Singh
  • Mahendra Pratap Kashyap
  • Vinay Kumar Tripathi
  • Sandeep Singh
  • Geetika Garg
  • Syed Ibrahim RizviEmail author


Autophagy is a catabolic process involved in the continuous removal of toxic protein aggregates and cellular organelles to maintain the homeostasis and functional integrity of cells. The mechanistic understanding of autophagy mediated neuroprotection during the development of neurodegenerative disorders remains elusive. Here, we investigated the potential role of rapamycin-induced activation of autophagy and PI3K/Akt1/mTOR/CREB pathway(s) in the neuroprotection of amyloid-beta (Aβ1-42)-insulted hippocampal neurons in rat model of Alzheimer’s disease (AD) like phenotypes. A single intra-hippocampal injection of Aβ1-42 impaired redox balance and markedly induced synaptic dysfunction, neurotransmission dysfunction, and cognitive deficit, and suppressed pro-survival signaling in the adult rats. Rapamycin administration caused a significant reduction of mTOR complex 1 phosphorylation at Ser2481 and a significant increase in levels of autophagy markers such as microtubule-associated protein-1 light chain-3 (LC3), beclin-1, sequestosome-1/p62, unc-51-like kinase 1 (ULK1). In addition, rapamycin induced the activation of autophagy that further activated p-PI3K, p-Akt1 (Ser473), and p-CREB (Ser183) expression in Aβ1-42-treated rats. The activated autophagy markedly reversed Aβ1-42-induced impaired redox homeostasis by decreasing the levels of prooxidants—ROS generation, intracellular Ca2+ flux and LPO, and increasing the levels of antioxidants—SOD, catalase, and GSH. The activated autophagy also provided significant neuroprotection against Aβ1-42-induced synaptic dysfunction by increasing the expression of synapsin-I, synaptophysin, and PSD95; and neurotransmission dysfunction by increasing the levels of CHRM2, DAD2 receptor, NMDA receptor, and AMPA receptor; and ultimately improved cognitive ability in rats. Wortmannin administration significantly reduced the expression of autophagy markers, p-PI3K, p-Akt1, and p-CREB, as well as the autophagy mediated neuroprotective effect. Our study demonstrate that autophagy can be an integrated part of pro-survival (PI3K/Akt1/mTOR/CREB) signaling and autophagic activation restores the oxidative defense mechanism(s), neurodegenerative damages, and maintains the integrity of synapse and neurotransmission in rat model of AD.


Amyloid-beta Autophagy Cognitive deficits Neurodegeneration Neuroprotection Rapamycin Synaptic dysfunction Wortmannin 



Dr. D. S. Kothari Post-Doctoral Fellowship scheme of the University Grant Commission, New Delhi, India, is acknowledged for providing financial support (F.4-2/2006(BSR)/BL/14-15/0326) and fellowship to Dr. A. K. Singh. The Department of Biochemistry, University of Allahabad is a recipient of the FIST grant from the DST SERB, Government of India.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Abhishek Kumar Singh
    • 1
  • Mahendra Pratap Kashyap
    • 2
  • Vinay Kumar Tripathi
    • 3
  • Sandeep Singh
    • 1
  • Geetika Garg
    • 1
  • Syed Ibrahim Rizvi
    • 1
    Email author
  1. 1.Department of BiochemistryUniversity of AllahabadAllahabadIndia
  2. 2.Department of UrologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of Animal Science and BiotechnologyChonbuk National UniversityJeonjuRepublic of Korea

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