PMID- 29331730 OWN - NLM STAT- MEDLINE DCOM- 20180927 LR - 20181202 IS - 1558-1497 (Electronic) IS - 0197-4580 (Linking) VI - 64 DP - 2018 Apr TI - Exenatide exerts cognitive effects by modulating the BDNF-TrkB neurotrophic axis in adult mice. PG - 33-43 LID - S0197-4580(17)30404-9 [pii] LID - 10.1016/j.neurobiolaging.2017.12.009 [doi] AB - Modulation of insulin-dependent signaling is emerging as a valuable therapeutic tool to target neurodegeneration. In the brain, the activation of insulin receptors promotes cell growth, neuronal repair, and protection. Altered brain insulin signaling participates in the cognitive decline seen in Alzheimer's disease patients and the aging brain. Glucagon-like peptide-1 (GLP-1) regulates insulin secretion and, along with GLP-1 analogues, enhances neurotrophic signaling and counteracts cognitive deficits in preclinical models of neurodegeneration. Moreover, recent evidence indicates that GLP-1 modulates the activity of the brain-derived neurotrophic factor (BDNF). In this study, in adult wild-type mice, here employed as a model of mid-life brain aging, we evaluated the effects of a 2-month treatment with exenatide, a GLP-1 analogue. We found that exenatide promotes the enhancement of long-term memory performances. Biochemical and imaging analyses show that the drug promotes the activation of the BDNF-TrkB neurotrophic axis and inhibits apoptosis by decreasing p75NTR-mediated signaling. The study provides preclinical evidence for the use of exenatide to delay age-dependent cognitive decline. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Bomba, Manuela AU - Bomba M AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy; Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Italy. FAU - Granzotto, Alberto AU - Granzotto A AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy; Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Italy. FAU - Castelli, Vanessa AU - Castelli V AD - Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy. FAU - Massetti, Noemi AU - Massetti N AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy. FAU - Silvestri, Elena AU - Silvestri E AD - Division of Pharmacology, Department of Science and Technology, University of Sannio, Benevento, Italy. FAU - Canzoniero, Lorella M T AU - Canzoniero LMT AD - Division of Pharmacology, Department of Science and Technology, University of Sannio, Benevento, Italy. FAU - Cimini, Annamaria AU - Cimini A AD - Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy; Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Temple University, Philadelphia, USA; National Institute for Nuclear Physics (INFN), Gran Sasso National Laboratory (LNGS), Assergi, Italy. FAU - Sensi, Stefano L AU - Sensi SL AD - Center of Excellence on Aging and Translational Medicine - CeSI-MeT, University G. d'Annunzio of Chieti-Pescara, Italy; Department of Neuroscience, Imaging, and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Italy; Departments of Neurology and Pharmacology, Institute for Mind Impairments and Neurological Disorders, University of California - Irvine, Irvine, USA. Electronic address: ssensi@uci.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171219 PL - United States TA - Neurobiol Aging JT - Neurobiology of aging JID - 8100437 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Membrane Glycoproteins) RN - 0 (Nootropic Agents) RN - 0 (Peptides) RN - 0 (Venoms) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 9P1872D4OL (Exenatide) RN - EC 2.7.10.1 (Ntrk2 protein, mouse) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (Receptor, Insulin) SB - IM MH - Animals MH - Brain/metabolism MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cells, Cultured MH - Cognition/*drug effects MH - Cognitive Aging MH - Cognitive Dysfunction/*drug therapy/etiology MH - Exenatide MH - Female MH - Glucagon-Like Peptide 1/analogs & derivatives/physiology MH - Hypoglycemic Agents/*pharmacology/*therapeutic use MH - Insulin/physiology MH - Male MH - Membrane Glycoproteins/*metabolism MH - Memory, Long-Term/*drug effects MH - Mice, Inbred Strains MH - *Nootropic Agents MH - Peptides/*pharmacology/*therapeutic use MH - Protein-Tyrosine Kinases/*metabolism MH - Receptor, Insulin/metabolism MH - Signal Transduction/drug effects/genetics MH - Venoms/*pharmacology/*therapeutic use OTO - NOTNLM OT - Cognitive enhancement OT - GLP-1 OT - GLP-1 receptor OT - Long-term potentiation OT - Type 2 diabetes mellitus EDAT- 2018/01/15 06:00 MHDA- 2018/09/28 06:00 CRDT- 2018/01/15 06:00 PHST- 2017/06/13 00:00 [received] PHST- 2017/12/07 00:00 [revised] PHST- 2017/12/08 00:00 [accepted] PHST- 2018/01/15 06:00 [pubmed] PHST- 2018/09/28 06:00 [medline] PHST- 2018/01/15 06:00 [entrez] AID - S0197-4580(17)30404-9 [pii] AID - 10.1016/j.neurobiolaging.2017.12.009 [doi] PST - ppublish SO - Neurobiol Aging. 2018 Apr;64:33-43. doi: 10.1016/j.neurobiolaging.2017.12.009. Epub 2017 Dec 19.