title: 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.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Allahabad, Allahabad, 211002, India.
authors.forename: Abhishek Kumar
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Mahendra Pratap
authors.initials: MP
authors.lastname: Kashyap
authors.affiliation: Department of Animal Science and Biotechnology, Chonbuk National University, Jeonju, 561-756, Republic of Korea.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Tripathi
authors.affiliation: Department of Biochemistry, University of Allahabad, Allahabad, 211002, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, University of Allahabad, Allahabad, 211002, India.
authors.forename: Geetika
authors.initials: G
authors.lastname: Garg
authors.affiliation: Department of Biochemistry, University of Allahabad, Allahabad, 211002, India. sirizvi@gmail.com.
authors.forename: Syed Ibrahim
authors.initials: SI
authors.lastname: Rizvi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546845:mTOR protein, rat; C494920:Akt1 protein, rat
keywords: Amyloid-beta; Autophagy; Cognitive deficits; Neurodegeneration; Neuroprotection; Rapamycin; Synaptic dysfunction; Wortmannin