PMID- 26790099 OWN - NLM STAT- MEDLINE DCOM- 20160811 LR - 20201215 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 1 DP - 2016 TI - Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport. PG - e0147250 LID - 10.1371/journal.pone.0147250 [doi] LID - e0147250 AB - Stress exposure or increased levels of corticotropin-releasing factor (CRF) induce hippocampal tau phosphorylation (tau-P) in rodent models, a process that is dependent on the type-1 CRF receptor (CRFR1). Although these preclinical studies on stress-induced tau-P provide mechanistic insight for epidemiological work that identifies stress as a risk factor for Alzheimer's disease (AD), the actual impact of stress-induced tau-P on neuronal function remains unclear. To determine the functional consequences of stress-induced tau-P, we developed a novel mouse neuronal cell culture system to explore the impact of acute (0.5hr) and chronic (2hr) CRF treatment on tau-P and integral cell processes such as axon transport. Consistent with in vivo reports, we found that chronic CRF treatment increased tau-P levels and caused globular accumulations of phosphorylated tau in dendritic and axonal processes. Furthermore, while both acute and chronic CRF treatment led to significant reduction in CREB activation and axon transport of brain-derived neurotrophic factor (BDNF), this was not the case with mitochondrial transport. Acute CRF treatment caused increased mitochondrial velocity and distance traveled in neurons, while chronic CRF treatment modestly decreased mitochondrial velocity and greatly increased distance traveled. These results suggest that transport of cellular energetics may take priority over growth factors during stress. Tau-P was required for these changes, as co-treatment of CRF with a GSK kinase inhibitor prevented CRF-induced tau-P and all axon transport changes. Collectively, our results provide mechanistic insight into the consequences of stress peptide-induced tau-P and provide an explanation for how chronic stress via CRF may lead to neuronal vulnerability in AD. FAU - Le, Michelle H AU - Le MH AD - Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America. FAU - Weissmiller, April M AU - Weissmiller AM AD - Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America. FAU - Monte, Louise AU - Monte L AD - Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America. FAU - Lin, Po Han AU - Lin PH AD - Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America. FAU - Hexom, Tia C AU - Hexom TC AD - Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America. FAU - Natera, Orlangie AU - Natera O AD - Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America. FAU - Wu, Chengbiao AU - Wu C AD - Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America. FAU - Rissman, Robert A AU - Rissman RA AD - Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, United States of America. AD - Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, United States of America. LA - eng GR - P50 AG005131/AG/NIA NIH HHS/United States GR - AG047484/AG/NIA NIH HHS/United States GR - AG005131/AG/NIA NIH HHS/United States GR - R01 AG032755/AG/NIA NIH HHS/United States GR - I01 BX003040/BX/BLRD VA/United States GR - AG010483/AG/NIA NIH HHS/United States GR - AG032755/AG/NIA NIH HHS/United States GR - U01 AG010483/AG/NIA NIH HHS/United States GR - R21 AG047484/AG/NIA NIH HHS/United States GR - BX003040/BX/BLRD VA/United States GR - PN2 EY016525/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160120 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Receptors, Corticotropin-Releasing Hormone) RN - 0 (tau Proteins) RN - 5CLY6W2H1M (CRF receptor type 1) RN - 9015-71-8 (Corticotropin-Releasing Hormone) SB - IM MH - Animals MH - Axonal Transport/drug effects/*physiology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cells, Cultured MH - Corticotropin-Releasing Hormone/*pharmacology MH - Female MH - Hippocampus/cytology/*drug effects/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Neurons/cytology/*drug effects/metabolism MH - Phosphorylation/drug effects MH - Receptors, Corticotropin-Releasing Hormone/metabolism MH - *Stress, Psychological MH - tau Proteins/*metabolism PMC - PMC4720402 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2016/01/21 06:00 MHDA- 2016/08/12 06:00 PMCR- 2016/01/20 CRDT- 2016/01/21 06:00 PHST- 2015/10/27 00:00 [received] PHST- 2016/01/03 00:00 [accepted] PHST- 2016/01/21 06:00 [entrez] PHST- 2016/01/21 06:00 [pubmed] PHST- 2016/08/12 06:00 [medline] PHST- 2016/01/20 00:00 [pmc-release] AID - PONE-D-15-47161 [pii] AID - 10.1371/journal.pone.0147250 [doi] PST - epublish SO - PLoS One. 2016 Jan 20;11(1):e0147250. doi: 10.1371/journal.pone.0147250. eCollection 2016.